Skip to main content
NIHPA Author Manuscripts logoLink to NIHPA Author Manuscripts
. Author manuscript; available in PMC: 2023 Sep 1.
Published in final edited form as: Semin Cell Dev Biol. 2021 May 9;129:31–39. doi: 10.1016/j.semcdb.2021.03.022

Olfactory modulation of the medial prefrontal cortex circuitry: implications for social cognition

Janardhan P Bhattarai 1, Semra Etyemez 2, Hanna Jaaro-Peled 2, Emma Janke 1, Usuy D Leon Tolosa 1, Atsushi Kamiya 2, Jay A Gottfried 5,6, Akira Sawa 2,3,4,*, Minghong Ma 1,*
PMCID: PMC8573060  NIHMSID: NIHMS1725944  PMID: 33975755

Abstract

Olfactory dysfunction is manifested in a wide range of neurological and psychiatric diseases, and often emerges prior to the onset of more classical symptoms and signs. From a behavioral perspective, olfactory deficits typically arise in conjunction with impairments of cognition, motivation, memory, and emotion. However, a conceptual framework for explaining the impact of olfactory processing on higher brain functions in health and disease remains lacking. Here we aim to provide circuit-level insights into this question by synthesizing recent advances in olfactory network connectivity with other cortical brain regions such as the prefrontal cortex. We will focus on social cognition as a representative model for exploring and critically evaluating the relationship between olfactory cortices and higher-order cortical regions in rodent models. Although rodents do not recapitulate all dimensions of human social cognition, they have experimentally accessible neural circuits and well-established behavioral tests for social motivation, memory/recognition, and hierarchy, which can be extrapolated to other species including humans. In particular, the medial prefrontal cortex (mPFC) has been recognized as a key brain region in mediating social cognition in both rodents and humans. This review will highlight the underappreciated connectivity, both anatomical and functional, between the olfactory system and mPFC circuitry, which together provide a neural substrate for olfactory modulation of social cognition and social behaviors. We will provide future perspectives on the functional investigation of the olfactory-mPFC circuit in rodent models and discuss how to translate such animal research to human studies.

Keywords: olfactory function, olfactory cortex, medial prefrontal cortex, social behaviors, social cognition, anterior olfactory nucleus, taenia tecta, neuropsychiatric diseases

1. Introduction

A large body of clinical literature reports olfactory dysfunction in neurological and psychiatric diseases, including Parkinson’s disease [1], Alzheimer’s disease [2], schizophrenia [3], mood disorders [4], and autism spectrum disorder [5]. Olfactory impairment often precedes other major disease symptoms and predicts disease severity. For example, olfactory function can be considered as a predictive marker of disease progression and prognosis in Parkinson’s disease [6] as well as in schizophrenia [7]. These clinical observations suggest that olfactory deficits may have primary pathogenic roles in these diseases. From a behavioral perspective, olfactory impairments coincide with deficits in cognition, motivation, memory, and emotion, presumably due to close connections between the olfactory system and other brain regions.

How the olfactory system interacts with other brain regions and thus influences higher cognitive functions is the topic of this review. Since deficits in social cognition are manifested in a variety of neurological and neuropsychiatric disorders [810], we will use social cognition as a lead dimension to provide in-depth discussion of the relationship between olfactory cortex and higher-order brain areas. Social cognition refers to the complex mental processes through which individuals perceive and respond to social signals from conspecifics. Here we use the term social cognition to include social motivation, social memory, and social hierarchy, common features described in numerous species. We will not cover species specific social behaviors such as those related to reproduction and parental care. It is worth noting that humans show unique higher-level social behaviors (e.g., empathy, mind reading, and moral judgement) that cannot be readily recapitulated in animal models. Humans have the ability to read subtle differences in facial expression and vocal tones as social cues and to infer mental states of self and others (known as theory of mind) [11, 12]. Nonetheless, common themes have emerged from human and animal studies on the neural circuitry involved in social cognition. In particular, the mPFC – spanning the anterior cingulate, prelimbic, and infralimbic cortices in the rodent brain, and homologous to human Brodmann Area 24, 32 and 25, respectively [13] – has been recognized as a key brain region in mediating social cognition across species [1416] (Table 1). The mPFC is implicated in working memory, motivation, decision making, and adaptive behaviors [17], essential elements for proper social behaviors. With experimentally accessible neural circuits and well-established behavioral tests, rodents provide invaluable preclinical animal models for social cognition studies.

Table 1.

Comparison of human and rodent mPFC subdivisions and brain regions receiving direct inputs from the olfactory bulb. The midcingulate cortex (MCC or BA 24’ in human; posterior to ACC, see Fig. 1) is not included here.

Human (BA: Brodmann Area) Rodent (Mouse and Rat)
Medial portion of the prefrontal cortex (mPFC)
Anterior cingulate cortex (ACC); BA 24 ACC*
Pregenual ACC (pACC); BA 32 Prelimbic cortex (PL)
Subgenual ACC (sACC); BA 25 Infralimbic cortex (IL)
Brain regions receiving direct inputs from the olfactory bulb (OB)
Anterior olfactory nucleus (AON) AON#
Taenia tecta (TT) Taenia tecta, ventral (TTv)
Taenia Tecta, dorsal (TTd)
Dorsal peduncular cortex (DP)^
Olfactory tubercle (OT) OT
Piriform cortex, frontal and temporal portion (Pir-F and Pir-T); BA27 Piriform cotex, anterior and posterior portion (aPir and pPir)
Amygdala (Amg) Anterior amygdalar area (AAA)
Piriform-amygdalar area (PAA); also called cortex-amygdala transition zone (CxA) or periamygdalar cortex
Nucleus of lateral olfactory tract (NLOT)
Bed nucleus of accessory olfactory tract (BAOT)
Medial amygdalar nucleus (MEA)
Cortical nucleus of amygdala (CoA; anterior and posterolateral divisions)
post-piriform transition area (TR); also called amygdalo-piriform transition area (AmPir)
Rostral Entorhinal Cortex (ventral BA 28, dorsal BA 34) lateral Entorhihnal Cortex (EC)
*

The rodent anterior cingulate gyrus can also be divided into Cg1 (dorsal) and Cg2 (ventral) spanning both ACC and MCC [13].

#

The rodent AON (also called anterior olfactory cortex [67]) is divided into the external and principal part, and the latter is further divided into the medial, dorsal, lateral, and ventroposterior division. The external part predominantly receives inputs from and projects to the contralateral OB, while the principal part communicates with ipsilateral OB as well as other brain regions.

^

The dorsal peduncular (DP) cortex was reported to receive direct OB inputs in earlier tracing studies [57]; however, this projection was potentially due to contamination from the AON, adjacent to the OB. A recent study with more restricted labeling of OB neurons did not confirm this projection [58]. Regardless, the DP is closely related to the olfactory system by receiving direct inputs either from the OB or from the AON.

A social behavior is typically triggered by sensory cues (olfactory, visual, auditory, somatosensory, etc.) that carry social information. In addition to sensing odors, the olfactory system also transmits nasal breathing signals into the brain [1821], which shapes oscillatory rhythmic brain activity even in the absence of odors [22, 23]. Recent studies highlight under-recognized network connections between the olfactory system and mPFC.

In this review, we will first provide a brief overview of the mPFC, the olfactory pathway, and their roles in social cognition. We will then discuss anatomical and functional connections from the olfactory system to the mPFC. Specifically, we will focus on the anterior olfactory cortical region (including the anterior olfactory nucleus and taenia tecta), which receives direct inputs from the olfactory bulb (the first olfactory synaptic relay) and projects to the mPFC. Lastly, we will discuss future directions on parsing the contribution of olfactory-mPFC connections in social cognition and other cognitive functions using modern neuroscience approaches, while considering the potential translation of rodent circuit-level understanding to human studies in health and disease.

2. The central role of mPFC in social cognition in rodents

Within the vast neural networks involved in social cognition, the mPFC has been recognized as a key regulator from rodents to humans [1416]. We use the term mPFC to include three distinct subdivisions: anterior cingulate, prelimbic, and infralimbic cortex in rodents, and their human homologous structures (summarized in Table 1). Although rodents lack the granular prefrontal cortex that is present in primates [24], the mPFC under this definition has anatomically and functionally homologous structures across species [13, 14, 16, 2426]. Since rodents have experimentally accessible neural circuits and well-established behavioral tests, investigation of the neural basis of rodent social behaviors is of high translational value. This review does not cover certain sex-specific social behaviors such as mating and parental care, which are recently reviewed elsewhere [27].

A variety of behavioral paradigms has been developed to assess social cognition in rodents, including social motivation (i.e., sociability or social preference), social recognition (i.e., social memory or social novelty preference), and social dominance (i.e., hierarchy). For example, in a three-chamber arena, a test mouse spends more time investigating a social object (a stranger mouse) than a non-social object, and thus providing a behavioral read-out of social preference or motivation [28]. Typically a juvenile same-sex mouse is used as the social object to avoid potential confounding factors in data interpretation (e.g., the test mouse may be submissive to the stranger mouse). When given the choice between a novel mouse and a familiar one, the mouse prefers interacting with the novel mouse, yielding a metric for assessing social recognition [28]. Social dominance can be assessed by placing two cage mates into a tube to observe that one mouse (dominant) forces the other one out (subordinate) [29]. Additionally, social defeat (i.e., chronic exposure to an aggressor) leads to social avoidance, anxiety, and depression-like behaviors [30]. Since these behaviors depend on internal drive as well as on learning and memory, social cognition contains both innate and acquired components.

Numerous studies suggest that the mPFC and its associated circuitry play a central role in social behaviors [14, 15]. The mPFC contains neural ensembles that dynamically code real-time social behaviroal information [31]. Direct manipulation of the activity of different subtypes of mPFC neurons impacts social approach and social interaction behaviors [32, 33], reflecting altered social motivation. In addition to glutamatergic and GABAergic synatpic transmission, the activity of mPFC neurons is also regulated by neuromodulators including dopamine, acetylcholine and oxytocin [14]. Oxytocin receptors are expressed in glutamatergic neurons in the mPFC and optogenetic activation of axons in the basolateral amygdala (originated from oxytocin receptor positive neurons in the mPFC) impairs social recognition [34]. The mPFC has strong connection with the hippocampus [17], which is essential for learning and memory consolidation to support social recognition [e.g., 35, 3641]. Similarly, the mPFC has been established as a key regulator in social dominance, likely through its connection with the mediodorsal thalamus [29, 42], as well as in social defeat-induced avoidance and anxiety-like behaviors through its connection with the amygdala, nucleus accumbens, and brainstem [4345]. The emerging picture suggests that each mPFC subdivision and its specific input and output pathways serve distinct functions in mediating social behaviors [e.g., 46, 47].

3. The olfactory pathway in rodents

The most comprehensive studies of anatomical and functional organization of the mammalian olfactory system have come from rodent models (mice and rats). The rodent nose contains several distinct chemosensory organs including the main olfactory epithelium (MOE) and vomeronasal organ (VNO), which express different types of chemoreceptors and transmit sensory information through the main and accessory olfactory system, respectively [reviewed in 48, 49]. The VNO detects pheromones, which signal social and/or sexual status of conspecifics, and downstream projections to the accessory olfactory pathway mediate species specific social behaviors such as mating and parental care [27, 50]. Because the VNO is non-functional in humans [51], this review is limited to discussion of the main olfactory system only.

The rodent MOE located in the posterior nasal cavity harbors approximately ten million olfactory sensory neurons (OSNs), each of which expresses a single type G protein-coupled odorant receptor from a repertoire of ~1200. OSNs respond to odor molecules as well as respiration-related nasal airflow and transduce sensory information into membrane potential changes and neuronal firing. The axons of OSNs expressing the same OR type typically project to two discrete glomeruli in the ipsilateral main olfactory bulb (OB), where they make synaptic contacts with OB neurons including mitral and tufted cells [52].

The OB efferent projections have been investigated via anterograde tracing from the OB neurons as well as retrograde tracing from the targeted regions [5358]. The axons of mitral and tufted cells form the lateral olfactory tract, which runs through the lateral part of the olfactory peduncle (the stalk connecting the OB with the basal forebrain) and projects to a number of cortical and subcortical regions (Figs. 1, 2). These regions are mostly three-layered structures including the anterior olfactory nucleus (AON), taenia tecta (TT), olfactory tubercle (OT, the most ventral part of the striatum), piriform cortex (Pir), amygdala, and entorhinal cortex (EC) (Table 1). The olfactory system contains parallel processing pathways. The mitral and tufted cells, the two types of projection neurons in the OB, project to different brain regions [59]. While mitral cells send elaborated axonal collaterals to almost all primary olfactory cortices, tufted cells predominantly target the anterior structures including the AON, TT and OT [6062] (Fig. 2). A subset of mitral cells in the posteroventral OB have been shown to transmit sex-related attractive social signals to the medial amygdala [63], but more studies are needed to distinguish the sensory information relayed by mitral and tufted cells.

Figure 1.

Figure 1.

Comparison of human and mouse mPFC and olfactory areas. A, Mouse whole-brain side view (tilted to view both sides) built from the Scalable Brain Atlas Composer (Allen Mouse Common Coordinate Framework v3) [157, 158]. B, A coronal section across the mPFC and some of the olfactory cortices [157]. C. Human whole-brain viewed from the midline, titled to better view the olfactory and mPFC areas. The mPFC areas are built from the Scalable Brain Atlas Composer (Human Brainnectome Atlas, Human-BN274) [159, 160], while the olfactory parts are added based on [161]. D and E, Coronal sections across the mPFC and some of the olfactory cortices [162]. The taenia tecta (TT) is added based on [159].

Abbreviations: MOB, main olfactory bulb; AON, anterior olfactory nucleus; TTd, taenia tecta dorsal; TTv, taenia tecta ventral; DP, dorsal peduncular cortex; mPFC, medial prefrontal cortex; IL, infra limbic; PL, prelimbic; ACC, anterior cingulate cortex; MCC, midcingulate cortex; OT, olfactory tubercle; aPir and pPir, anterior and posterior piriform cortex; Amg, amygdala; CoA, cortical amygdala; EC, entorhinal cortex; MD mediodorsal nucleus of thalamus; Hip, hippocampus; BA, Brodmann area; OB, olfactory bulb; Pir-F, piriform cortex frontal lobe; Pir-T, piriform cortex temporal lobe.

Figure 2.

Figure 2.

Potential connections from the olfactory pathway to the mPFC in rodents. Arrow lines start from neuronal cell bodies and end in axonal targets. Note that most connections are reciprocal. For clarity, not all connections are shown.

Abbreviations: OE, olfactory epithelium; MOB, main olfactory bulb; T, tufted cells; M, mitral cells; AON, anterior olfactory nucleus; TTd, taenia tecta dorsal; TTv, taenia tecta ventral; DP, dorsal peduncular cortex; mPFC, medial prefrontal cortex; IL, infralimbic cortex; PL prelimbic cortex; ACC, anterior cingulate cortex; OT, olfactory tubercle; Pir, piriform cortex; Amg, amygdala; EC, entorhinal cortex; MD, mediodorsal thalamic nucleus; Hip, hippocampus; OFC, orbitofrontal cortex.

There are several noteworthy features of the olfactory pathway. (1) Unlike other sensory modalities, olfactory information is transmitted to the cortices without a thalamic relay. For example, the Pir transmits the sensory information to the orbitofrontal cortex (OFC) directly, although there is a minor pathway via the mediodorsal thalamic nucleus [64]. (2) The fact that the OB projects to multiple olfactory cortices suggests parallel processing of olfactory information. The olfactory regions including the OB, primary cortices, and OFC, are extensively interconnected [6567]. The recurrent connections provide feedforward and feedback signals to the olfactory network and enable one region (e.g., AON) to impact the activity of the other regions (e.g., Pir) [68, 69]. (3) The OB receives extensive top-down inputs not only from olfactory cortices, but also from neuromodulatory centers (e.g., serotonin from raphe nuclei, acetylcholine from basal forebrain, and norepinephrine from locus coeruleus) [57, 70, 71], underscoring that the peripheral olfactory input is highly regulated by the brain state and experience [7274]. (4) Only a few synapses separate OSNs from neurons that ultimately drive behavioral outputs and hormone changes [e.g., 75, 76, 77]. Moreover, the olfactory system has strong connections with the limbic system as well as the mPFC, which is discussed in-depth below.

4. Olfactory contributions to social cognition in rodents

Social behaviors in rodents predominantly rely on chemosensory cues released from conspecifics. These chemosensory cues range from small volatile molecules to large non-volatile proteins coming from a variety of sources (e.g., urine, feces, skin, and glands) [78]. Although multiple chemosensory organs in the nose detect these social cues, the main olfactory system is critical for social behaviors by detecting and processing both volatile and non-volatile molecules [79, 80]. Here we focus on potential contributions of primary olfactory cortices to social cognition beyond detection and processing of these social cues.

The OT encodes odor valence and reward information, and promotes motivational behavior [8183]. Social interaction leads to increased Ca2+ signals of the dopaminergic projection from the ventral tegmental area to the OT [84]. The Pir is essential for learned associations between odor and socially significant cues via oxytocin receptor signaling [85]. Notably, the AON plays an important role in social behaviors via several subtypes of neurons. Oxytocin receptor-expressing neurons in the AON receive direct projections from oxytocin neurons in the hypothalamus. Consequently, oxytocin excites these neurons and increases top-down inhibition onto OB granule cells. This signaling ultimately increases the signal-to-noise ratio for social cue-induced OB activity, and deletion of oxytocin receptors in the AON impairs social recognition memory [86]. A recent study on male mice with stable linear dominance hierarchy (alpha, subdominant, and subordinate) shows that the alpha mice had a higher level of oxytocin receptor binding in the AON [87], suggesting potential involvement of this brain region in social hierachy. In addition, exposure to a juvenile rat (but not to non-social objects) activates GABAergic, vasopressin expressing neurons in the AON [88]. Furthermore, the medial AON contributes to odor memory and social behaviors via direct projection from the ventral hippocampus [89, 90]. Taken together, in addition to detecting and processing social cues, the central olfactory circuits also contribute to social cognition through their connections with other brain regions.

5. Olfactory influences on mPFC circuitry in rodents

5.1. Anatomical evidence supporting olfactory-mPFC connections

Whole-brain afferents to the rodent mPFC have been analyzed via retrograde tracing [e.g., 91, 92, 93]. By focally injecting Fluorogold into each subdivision of the rat mPFC, Hoover and Vertes [91] found that the inputs along the dorsoventral axis shift from more sensorimotor inputs to the ACC to more limbic inputs to the prelimbic and infralimbic cortex. Differential inputs into different subregions of the mPFC are recently confirmed in mice [93]. Using rabies virus-based trans-synaptic tracing, whole-brain afferent inputs into different subtypes of neurons in the mPFC have been quantified [92, 93]. The long-range projections to the mPFC come from the entire neocortex, thalamus, striatum and pallidum, hippocampus, hypothalamus, and amygdala, as well as olfactory primary cortices (TT, AON and Pir) [92, 93].

Based on the current understanding of the mPFC connectivity, the primary olfactory cortices can transmit information to the mPFC via the relay of multiple regions, including the OFC, thalamus, hippocampus, and amygdala (Fig. 2). More importantly, the anterior olfactory cortical region (i.e., AON and TT [94]), which have been traditionally more neglected than other olfactory regions, has physical proximity to the mPFC and provides a more direct pathway linking the olfactory system and the mPFC. Retrograde tracing from the mPFC identifies presynaptic cells in the AON and TT [91, 92, 95, 96]. The projection from the AON to the mPFC (PL and IL) is also further confirmed by anterograde tracing via viral infection of glutamatergic neurons in the AON and TT [96]. Interestingly, the tufted cells in the OB primarily project to the anterior olfactory cortical region while the mitral cells project broadly. Since tufted cells receive stronger peripheral inputs [97] and display robust respiration-entrained rhythms and odor-induced responses [98, 99], it is tempting to propose that the OB tufted cells, via the relay of the anterior olfactory cortical region, carry olfactory information to the mPFC and serve distinct functions. In addition, a direct projection from the posterior Pir to mPFC has been reported to play a critical role in social transmission of food safety [100].

5.2. Functional evidence supporting olfactory-mPFC connections

Until now, the functional evidence that supports olfactory modulation of mPFC activity mainly comes from respiration-entrained olfactory signals in the context of odor-independent behaviors. The mPFC displays a predominant respiration-coupled activity during the immobility phase of the tail-suspension test [95, 101] or during auditory-cued, conditioned fear-induced freezing bouts [96, 102, 103]. Bulbectomy or ablation of the olfactory epithelium significantly reduces respiration-related activity in the mPFC [95, 96, 102, 103], highlighting a major contribution from the olfactory pathway even though there are multiple sources of respiratory rhythms in the brain [104]. Furthermore, optogenetic activation of OSNs in the olfactory epithelium is sufficient to entrain mPFC activity at the stimulating frequencies [96]. These findings strongly support that the olfactory input modulates mPFC activity.

Social behaviors depend on chemosensory cues, and rodents change their breathing/sniffing patterns during odor investigation [105, 106]. For instance, in a social hierarchy test, subordinate rats decrease their sniffing frequency when facing dominant rats [107]. Repeated social defeat leads to long-lasting bradypnea, an abnormally slow breathing rate in rats [108]. It is plausible that during social behaviors, both odor-induced and respiration-related olfactory signals may modulate mPFC activity. The different breathing patterns may differentially modulate the activity of the mPFC circuitry and influence the behavioral outcome. Alternatively, social factors may modulate mPFC activity through non-olfactory pathways to influence motor output related to olfaction/respiration. To differentiate the contribution of olfactory (odor-induced or respiration-related) versus non-olfactory input to mPFC activity, experimental manipulation of specific neural circuit(s) mediating one input at a time in social behaviors is required in future studies.

5.3. Olfactory influence on other parts of the mPFC circuitry involved in social cognition

The mPFC has widespread projections to subcortical regions (e.g., hippocampus, amygdala, hypothalamus, nucleus accumbens, ventral tegmental area, and neuromodulatory centers) that are crucial for memory, emotion, motivation, decision making, and adaptive behavior [1416]. The olfactory pathway also has close connections with these subcortical regions [109, 110]. For example, the OB projects directly to the entorhinal cortex, which provides major inputs to the hippocampus, and the hippocampus also sends strong projections to the olfactory regions [111], including the OB [112]. Recent studies reveal that the ventral hippocampus to the AON projection plays an important role in odor memory and olfactory-guided behaviors [89, 90]. Similarly, through direct projections to subregions of the amygdala [113], the olfactory pathway potentially modulates the neural activity in the basolateral amygdala and mPFC circuitry. Moreover, the activity of most neural networks (including the olfactory system and mPFC circuitry) is also regulated by the neuromodulatory centers in the brainstem in a state- and context-dependent manner [114, 115]. For instance, the reward effect of social interaction activates serotonergic neurons in the dorsal raphe nucleus [116], which may in turn modulate sensory input and mPFC activity to influence behavioral output. During specific behaviors, the neural activity in multiple brain regions often becomes transiently synchronized [117, 118], which has been demonstrated repeatedly in the mPFC and its associated neural network [17, 118]. Respiration-coupled olfactory signals provide a low-frequency rhythmic activity to coordinate the network activity among the mPFC and its associated subcortical brain structures. A recent study reveals that mPFC activity from two socially interacting mice is correlated [119], and it would be interesting to determine whether social partners also have synchronized respiration and/or neural activity in their olfactory pathways.

6. Implications for olfactory contributions to social cognition in humans

In addition to olfactory cues, humans also rely on visual and auditory cues (e.g., facial expression and vocal tones) to interpret the mental states of others in social settings. It is conceivable that visual and/or auditory dysfunction is associated with compromised social cognition in diseased conditions [e.g.,120]. Curiously, olfactory dysfunction is characteristic in a wide range of neurological and psychiatric diseases (see Introduction for references). The close network connection between the olfactory pathway to higher brain regions (including but not limited to mPFC) may provide a clue to the underlying mechanisms.

Compared to the rodent brain, anatomical and functional organization of the human olfactory pathway is less understood. This is partly due to the small sizes of olfactory regions relative to the rest of the brain and their mostly ventral location at the base of the brain. Nevertheless, primary olfactory cortices (including the AON, OT, Pir, and subregions of both the amygdala and entorhinal cortex) as well as the OFC have been investigated anatomically and functionally [121129] (Table 1 and Fig. 1). A recent study using functional magnetic resonance imaging (fMRI) from healthy human subjects clustered the subdivisions of primary olfactory cortices based on resting-state, whole-brain functional connectivity patterns, providing preliminary support for identifying the presumptive AON, OT, and Pir (frontal and temporal divisions) [130] (Fig. 1). More task-based fMRI studies are needed to dissect out distinct roles of each primary olfactory region and their connections with other brain regions including the mPFC. Interestingly, even though humans breathe at a much slower rate (0.1–0.3 Hz) compared to rodents (2–12 Hz), nasal (but not oral) breathing is effective in entraining the neural activity in the olfactory and limbic system of the human brain and modulating cognitive functions [131, 132]. These findings underscore that the olfactory system can impact brain activity in the absence of odors via involuntary or voluntary changes in respiration.

Studies in healthy individuals have linked alteration of olfactory function to changes in memory, language, and executive function, which include cognitive inflexibility, higher impulsivity, and lower behavioral inhibitory control [133136]. Other studies also link olfactory dysfunction to impaired perception of olfactory signals, emotions, and reduced social network size [137142]. It is unclear how much these changes are related to the observations in rodents described above, in particular in association with social cognition. However, an overlap of brain circuits in olfactory function and those in social cognition exists particularly in limbic and paralimbic brain regions [130]. Some studies reported that functional connectivity of amygdala with OFC has been related to both olfactory function (sensitivity) and social network size [142, 143]. In addition, activation of the mPFC and OFC has been observed during olfactory memory tests and subjective perception of pleasantness of odors [144]. Future studies with independent validation cohorts will evaluate these interesting ideas or working hypotheses proposed by the aforementioned pioneer works.

Olfactory dysfunction and social cognition deficits have been intensively studied as separate and independent topics in psychiatric disorders, yet little is known about how these functions interact with each other. As far as we are aware, three reports have been published on these interactions in patients with schizophrenia in a cross-sectional design. One study demonstrates a significant association of odor identification with theory of mind and face recognition in social cognition domains [145], and the other two studies report a significant relationship of odor identification with facial affect recognition [146, 147]. In addition, similar findings are reported in other psychiatric conditions such as bipolar disorder and autism spectrum disorder [148151]. Although these human studies are informative, the descriptive nature of these studies do not provide mechanistic insights, in particular those translatable with rodents. Again, these clinical studies are expected to be further validated by other independent cohorts or meta-analyses. Brain imaging combined with olfactory functional and cognitive tests may be a route to address mechanisms.

7. Perspectives

Recent technological advances in neuroscience research make it feasible to study the neural basis of complex behaviors at the molecular, cellular, and circuit levels in rodent models. In the context of social cognition and social behavior, we propose that contributions of the olfactory system reach beyond detection and perception of social cues. Through its critical link with the mPFC and its circuitry, the olfactory pathway significantly impacts social cognition even in species that do not heavily rely on olfactory cues. A better understanding of olfactory modulation on the mPFC circuitry will offer novel mechanistic insights into how olfactory dysfunction is frequently observed in early stages of neuropsychiatric disorders and holds potential predictive significance.

To achieve this goal, several questions in basic science remain to be addressed. First, given the almost non-overlapping cortical and subcortical targets of OB mitral and tufted cells, do they relay distinct sensory information in social behaviors? Second, among the multiple pathways through which information flows from primary olfactory cortices to the mPFC, does the anterior olfactory cortical region (i.e., AON and TT) serve a special function? It is important to identify specific molecular marker(s) to gain genetic access to these neurons. One can further dissect out circuit connections of these neurons to each subdivision of the mPFC and test the effects of optogenetic and/or chemogenetic activation and inactivation on mPFC activity and social behaviors. Third, how to separate odor- and respiration-related contributions of the olfactory system to social cognition? Both odor-dependent and odor-independent behaviors need to be tested, and mPFC activity needs to be monitored concurrently with the respiration signal.

Whether olfactory dysfunction contributes to neurological and psychiatric disorders in a causal manner or is one of the symptoms, reflecting central neuropathological abnormalities, cannot be easily answered in human studies, whereas in rodent models, we can manipulate the olfactory circuitry and test the effects on higher-order brain areas and cognitive behaviors. In some mouse models in which disease-associated genes are disrupted, both olfactory and social deficits have been reported [152, 153]. However, their causal relationship also remains elusive. It is important to test this idea by using rodent models in which olfactory deficits are specifically introduced, while examining resultant changes of social behaviors. The bulbectomy model in which the OB is surgically impaired has been considered in this line of efforts [154, 155]. However, the technology of the frontline neuroscience may provide more specific, less invasive models for testing a causal role of olfactory deficits in social behaviors.

Despite our focus on social cognition in this review, neural connectivity between the olfactory system and mPFC also likely contributes to other cognitive functions [e.g., 156]. Olfactory modulation of brain activity and higher cognition warrants future investigations in preclinical animal models and humans.

Acknowledgement

This work is supported by NIDCD (R01DC006213 to MM, R21DC019193 to JPB, and R01DC018075 to JAG), NIMH (P50MH094268, R01MH105660, and R01MH107730 to AS), NIDA (R01DA049545 and R01DA049449 to MM, R01DA041208 to AK), NIA (R01AG065168 to AK), and foundation grants from Stanley and RUSK/S-R (to AS).

Footnotes

Declarations of interest: none.

References

  • [1].Doty RL, Olfactory dysfunction in Parkinson disease, Nat Rev Neurol 8(6) (2012) 329–39. [DOI] [PubMed] [Google Scholar]
  • [2].Murphy C, Olfactory and other sensory impairments in Alzheimer disease, Nat Rev Neurol 15(1) (2019) 11–24. [DOI] [PubMed] [Google Scholar]
  • [3].Moberg PJ, Kamath V, Marchetto DM, Calkins ME, Doty RL, Hahn CG, Borgmann-Winter KE, Kohler CG, Gur RE, Turetsky BI, Meta-analysis of olfactory function in schizophrenia, first-degree family members, and youths at-risk for psychosis, Schizophr Bull 40(1) (2014) 50–9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [4].Kohli P, Soler ZM, Nguyen SA, Muus JS, Schlosser RJ, The Association Between Olfaction and Depression: A Systematic Review, Chem Senses 41(6) (2016) 479–86. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [5].Crow AJD, Janssen JM, Vickers KL, Parish-Morris J, Moberg PJ, Roalf DR, Olfactory Dysfunction in Neurodevelopmental Disorders: A Meta-analytic Review of Autism Spectrum Disorders, Attention Deficit/Hyperactivity Disorder and Obsessive-Compulsive Disorder, J Autism Dev Disord 50(8) (2020) 2685–2697. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [6].Postuma RB, Berg D, Advances in markers of prodromal Parkinson disease, Nat Rev Neurol 12(11) (2016) 622–634. [DOI] [PubMed] [Google Scholar]
  • [7].Lin A, Brewer WJ, Yung AR, Nelson B, Pantelis C, Wood SJ, Olfactory identification deficits at identification as ultra-high risk for psychosis are associated with poor functional outcome, Schizophr Res 161(2–3) (2015) 156–62. [DOI] [PubMed] [Google Scholar]
  • [8].Kennedy DP, Adolphs R, The social brain in psychiatric and neurological disorders, Trends Cogn Sci 16(11) (2012) 559–72. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [9].Bora E, Pantelis C, Social cognition in schizophrenia in comparison to bipolar disorder: A meta-analysis, Schizophr Res 175(1–3) (2016) 72–78. [DOI] [PubMed] [Google Scholar]
  • [10].Green MF, Horan WP, Lee J, Social cognition in schizophrenia, Nat Rev Neurosci 16(10) (2015) 620–31. [DOI] [PubMed] [Google Scholar]
  • [11].Beaudoin C, Leblanc E, Gagner C, Beauchamp MH, Systematic Review and Inventory of Theory of Mind Measures for Young Children, Front Psychol 10 (2019) 2905. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [12].Byom LJ, Mutlu B, Theory of mind: mechanisms, methods, and new directions, Front Hum Neurosci 7 (2013) 413. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [13].van Heukelum S, Mars RB, Guthrie M, Buitelaar JK, Beckmann CF, Tiesinga PHE, Vogt BA, Glennon JC, Havenith MN, Where is Cingulate Cortex? A Cross-Species View, Trends Neurosci 43(5) (2020) 285–299. [DOI] [PubMed] [Google Scholar]
  • [14].Bicks LK, Koike H, Akbarian S, Morishita H, Prefrontal Cortex and Social Cognition in Mouse and Man, Front Psychol 6 (2015) 1805. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [15].Ko J, Neuroanatomical Substrates of Rodent Social Behavior: The Medial Prefrontal Cortex and Its Projection Patterns, Front Neural Circuits 11 (2017) 41. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [16].Amodio DM, Frith CD, Meeting of minds: the medial frontal cortex and social cognition, Nat Rev Neurosci 7(4) (2006) 268–77. [DOI] [PubMed] [Google Scholar]
  • [17].Euston DR, Gruber AJ, McNaughton BL, The role of medial prefrontal cortex in memory and decision making, Neuron 76(6) (2012) 1057–70. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [18].Grosmaitre X, Santarelli LC, Tan J, Luo M, Ma M, Dual functions of mammalian olfactory sensory neurons as odor detectors and mechanical sensors, Nature neuroscience 10(3) (2007) 348–54. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [19].Iwata R, Kiyonari H, Imai T, Mechanosensory-Based Phase Coding of Odor Identity in the Olfactory Bulb, Neuron 96(5) (2017) 1139–1152 e7. [DOI] [PubMed] [Google Scholar]
  • [20].Wu R, Liu Y, Wang L, Li B, Xu F, Activity Patterns Elicited by Airflow in the Olfactory Bulb and Their Possible Functions, J Neurosci 37(44) (2017) 10700–10711. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [21].Connelly T, Yu Y, Grosmaitre X, Wang J, Santarelli LC, Savigner A, Qiao X, Wang Z, Storm DR, Ma M, G protein-coupled odorant receptors underlie mechanosensitivity in mammalian olfactory sensory neurons, Proc Natl Acad Sci U S A 112(2) (2015) 590–5. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [22].Tort ABL, Brankack J, Draguhn A, Respiration-Entrained Brain Rhythms Are Global but Often Overlooked, Trends Neurosci 41(4) (2018) 186–197. [DOI] [PubMed] [Google Scholar]
  • [23].Varga S, Heck DH, Rhythms of the body, rhythms of the brain: Respiration, neural oscillations, and embodied cognition, Conscious Cogn 56 (2017) 77–90. [DOI] [PubMed] [Google Scholar]
  • [24].Wise SP, Forward frontal fields: phylogeny and fundamental function, Trends Neurosci 31(12) (2008) 599–608. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [25].Brown VJ, Bowman EM, Rodent models of prefrontal cortical function, Trends Neurosci 25(7) (2002) 340–3. [DOI] [PubMed] [Google Scholar]
  • [26].Laubach M, Amarante LM, Swanson K, White SR, What, If Anything, Is Rodent Prefrontal Cortex?, eNeuro 5(5) (2018). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [27].Li Y, Dulac C, Neural coding of sex-specific social information in the mouse brain, Curr Opin Neurobiol 53 (2018) 120–130. [DOI] [PubMed] [Google Scholar]
  • [28].Moy SS, Nadler JJ, Perez A, Barbaro RP, Johns JM, Magnuson TR, Piven J, Crawley JN, Sociability and preference for social novelty in five inbred strains: an approach to assess autistic-like behavior in mice, Genes Brain Behav 3(5) (2004) 287–302. [DOI] [PubMed] [Google Scholar]
  • [29].Wang F, Zhu J, Zhu H, Zhang Q, Lin Z, Hu H, Bidirectional control of social hierarchy by synaptic efficacy in medial prefrontal cortex, Science 334(6056) (2011) 693–7. [DOI] [PubMed] [Google Scholar]
  • [30].Krishnan V, Han MH, Graham DL, Berton O, Renthal W, Russo SJ, Laplant Q, Graham A, Lutter M, Lagace DC, Ghose S, Reister R, Tannous P, Green TA, Neve RL, Chakravarty S, Kumar A, Eisch AJ, Self DW, Lee FS, Tamminga CA, Cooper DC, Gershenfeld HK, Nestler EJ, Molecular adaptations underlying susceptibility and resistance to social defeat in brain reward regions, Cell 131(2) (2007) 391–404. [DOI] [PubMed] [Google Scholar]
  • [31].Liang B, Zhang L, Barbera G, Fang W, Zhang J, Chen X, Chen R, Li Y, Lin DT, Distinct and Dynamic ON and OFF Neural Ensembles in the Prefrontal Cortex Code Social Exploration, Neuron 100(3) (2018) 700–714 e9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [32].Yizhar O, Fenno LE, Prigge M, Schneider F, Davidson TJ, O’Shea DJ, Sohal VS, Goshen I, Finkelstein J, Paz JT, Stehfest K, Fudim R, Ramakrishnan C, Huguenard JR, Hegemann P, Deisseroth K, Neocortical excitation/inhibition balance in information processing and social dysfunction, Nature 477(7363) (2011) 171–8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [33].Liu L, Xu H, Wang J, Li J, Tian Y, Zheng J, He M, Xu TL, Wu ZY, Li XM, Duan SM, Xu H, Cell type-differential modulation of prefrontal cortical GABAergic interneurons on low gamma rhythm and social interaction, Sci Adv 6(30) (2020) eaay4073. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [34].Tan Y, Singhal SM, Harden SW, Cahill KM, Nguyen DM, Colon-Perez LM, Sahagian TJ, Thinschmidt JS, de Kloet AD, Febo M, Frazier CJ, Krause EG, Oxytocin Receptors Are Expressed by Glutamatergic Prefrontal Cortical Neurons That Selectively Modulate Social Recognition, J Neurosci 39(17) (2019) 3249–3263. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [35].Kogan JH, Frankland PW, Silva AJ, Long-term memory underlying hippocampus-dependent social recognition in mice, Hippocampus 10(1) (2000) 47–56. [DOI] [PubMed] [Google Scholar]
  • [36].Hitti FL, Siegelbaum SA, The hippocampal CA2 region is essential for social memory, Nature 508(7494) (2014) 88–92. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [37].Suzuki A, Fukushima H, Mukawa T, Toyoda H, Wu LJ, Zhao MG, Xu H, Shang Y, Endoh K, Iwamoto T, Mamiya N, Okano E, Hasegawa S, Mercaldo V, Zhang Y, Maeda R, Ohta M, Josselyn SA, Zhuo M, Kida S, Upregulation of CREB-mediated transcription enhances both short- and long-term memory, J Neurosci 31(24) (2011) 8786–802. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [38].Garrido Zinn C, Clairis N, Silva Cavalcante LE, Furini CR, de Carvalho Myskiw J, Izquierdo I, Major neurotransmitter systems in dorsal hippocampus and basolateral amygdala control social recognition memory, Proc Natl Acad Sci U S A 113(33) (2016) E4914–9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [39].Tanimizu T, Kenney JW, Okano E, Kadoma K, Frankland PW, Kida S, Functional Connectivity of Multiple Brain Regions Required for the Consolidation of Social Recognition Memory, J Neurosci 37(15) (2017) 4103–4116. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [40].Felix-Ortiz AC, Tye KM, Amygdala inputs to the ventral hippocampus bidirectionally modulate social behavior, J Neurosci 34(2) (2014) 586–95. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [41].Phillips ML, Robinson HA, Pozzo-Miller L, Ventral hippocampal projections to the medial prefrontal cortex regulate social memory, Elife 8 (2019). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [42].Zhou T, Zhu H, Fan Z, Wang F, Chen Y, Liang H, Yang Z, Zhang L, Lin L, Zhan Y, Wang Z, Hu H, History of winning remodels thalamo-PFC circuit to reinforce social dominance, Science 357(6347) (2017) 162–168. [DOI] [PubMed] [Google Scholar]
  • [43].Felix-Ortiz AC, Burgos-Robles A, Bhagat ND, Leppla CA, Tye KM, Bidirectional modulation of anxiety-related and social behaviors by amygdala projections to the medial prefrontal cortex, Neuroscience 321 (2016) 197–209. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [44].Franklin TB, Silva BA, Perova Z, Marrone L, Masferrer ME, Zhan Y, Kaplan A, Greetham L, Verrechia V, Halman A, Pagella S, Vyssotski AL, Illarionova A, Grinevich V, Branco T, Gross CT, Prefrontal cortical control of a brainstem social behavior circuit, Nat Neurosci 20(2) (2017) 260–270. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [45].Vialou V, Bagot RC, Cahill ME, Ferguson D, Robison AJ, Dietz DM, Fallon B, Mazei-Robison M, Ku SM, Harrigan E, Winstanley CA, Joshi T, Feng J, Berton O, Nestler EJ, Prefrontal cortical circuit for depression- and anxiety-related behaviors mediated by cholecystokinin: role of DeltaFosB, J Neurosci 34(11) (2014) 3878–87. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [46].Huang WC, Zucca A, Levy J, Page DT, Social Behavior Is Modulated by Valence-Encoding mPFC-Amygdala Sub-circuitry, Cell Rep 32(2) (2020) 107899. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [47].Rudebeck PH, Walton ME, Millette BH, Shirley E, Rushworth MF, Bannerman DM, Distinct contributions of frontal areas to emotion and social behaviour in the rat, Eur J Neurosci 26(8) (2007) 2315–26. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [48].Ma M, Encoding olfactory signals via multiple chemosensory systems, Crit Rev Biochem Mol Biol 42(6) (2007) 463–80. [DOI] [PubMed] [Google Scholar]
  • [49].Munger SD, Leinders-Zufall T, Zufall F, Subsystem organization of the mammalian sense of smell, Annu Rev Physiol 71 (2009) 115–40. [DOI] [PubMed] [Google Scholar]
  • [50].Mohrhardt J, Nagel M, Fleck D, Ben-Shaul Y, Spehr M, Signal Detection and Coding in the Accessory Olfactory System, Chem Senses 43(9) (2018) 667–695. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [51].Bhatnagar KP, Smith TD, The human vomeronasal organ. III. Postnatal development from infancy to the ninth decade, J Anat 199(Pt 3) (2001) 289–302. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [52].Mori K, Sakano H, Olfactory Circuitry and Behavioral Decisions, Annu Rev Physiol 83 (2021) 231–256. [DOI] [PubMed] [Google Scholar]
  • [53].Sosulski DL, Bloom ML, Cutforth T, Axel R, Datta SR, Distinct representations of olfactory information in different cortical centres, Nature 472(7342) (2011) 213–6. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [54].Miyamichi K, Amat F, Moussavi F, Wang C, Wickersham I, Wall NR, Taniguchi H, Tasic B, Huang ZJ, He Z, Callaway EM, Horowitz MA, Luo L, Cortical representations of olfactory input by trans-synaptic tracing, Nature 472(7342) (2011) 191–6. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [55].Ghosh S, Larson SD, Hefzi H, Marnoy Z, Cutforth T, Dokka K, Baldwin KK, Sensory maps in the olfactory cortex defined by long-range viral tracing of single neurons, Nature 472(7342) (2011) 217–20. [DOI] [PubMed] [Google Scholar]
  • [56].Cadiz-Moretti B, Abellan-Alvaro M, Pardo-Bellver C, Martinez-Garcia F, Lanuza E, Afferent and Efferent Connections of the Cortex-Amygdala Transition Zone in Mice, Front Neuroanat 10 (2016) 125. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [57].Shipley MT, Ennis M, Functional organization of olfactory system, J Neurobiol 30(1) (1996) 123–76. [DOI] [PubMed] [Google Scholar]
  • [58].Hintiryan H, Gou L, Zingg B, Yamashita S, Lyden HM, Song MY, Grewal AK, Zhang X, Toga AW, Dong HW, Comprehensive connectivity of the mouse main olfactory bulb: analysis and online digital atlas, Front Neuroanat 6 (2012) 30. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [59].Imamura F, Ito A, LaFever BJ, Subpopulations of Projection Neurons in the Olfactory Bulb, Front Neural Circuits 14 (2020) 561822. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [60].Nagayama S, Enerva A, Fletcher ML, Masurkar AV, Igarashi KM, Mori K, Chen WR, Differential axonal projection of mitral and tufted cells in the mouse main olfactory system, Front Neural Circuits 4 (2010). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [61].Igarashi KM, Ieki N, An M, Yamaguchi Y, Nagayama S, Kobayakawa K, Kobayakawa R, Tanifuji M, Sakano H, Chen WR, Mori K, Parallel mitral and tufted cell pathways route distinct odor information to different targets in the olfactory cortex, J Neurosci 32(23) (2012) 7970–85. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [62].Scott JW, Ranier EC, Pemberton JL, Orona E, Mouradian LE, Pattern of rat olfactory bulb mitral and tufted cell connections to the anterior olfactory nucleus pars externa, The Journal of comparative neurology 242(3) (1985) 415–24. [DOI] [PubMed] [Google Scholar]
  • [63].Inokuchi K, Imamura F, Takeuchi H, Kim R, Okuno H, Nishizumi H, Bito H, Kikusui T, Sakano H, Nrp2 is sufficient to instruct circuit formation of mitral-cells to mediate odour-induced attractive social responses, Nat Commun 8 (2017) 15977. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [64].Courtiol E, Wilson DA, The olfactory thalamus: unanswered questions about the role of the mediodorsal thalamic nucleus in olfaction, Front Neural Circuits 9 (2015) 49. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [65].Haberly LB, Price JL, Association and commissural fiber systems of the olfactory cortex of the rat. II. Systems originating in the olfactory peduncle, J Comp Neurol 181(4) (1978) 781–807. [DOI] [PubMed] [Google Scholar]
  • [66].Haberly LB, Price JL, Association and commissural fiber systems of the olfactory cortex of the rat, J Comp Neurol 178(4) (1978) 711–40. [DOI] [PubMed] [Google Scholar]
  • [67].Haberly LB, Parallel-distributed processing in olfactory cortex: new insights from morphological and physiological analysis of neuronal circuitry, Chemical senses 26(5) (2001) 551–76. [DOI] [PubMed] [Google Scholar]
  • [68].Franks KM, Russo MJ, Sosulski DL, Mulligan AA, Siegelbaum SA, Axel R, Recurrent circuitry dynamically shapes the activation of piriform cortex, Neuron 72(1) (2011) 49–56. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [69].Poo C, Isaacson JS, A major role for intracortical circuits in the strength and tuning of odor-evoked excitation in olfactory cortex, Neuron 72(1) (2011) 41–8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [70].McIntyre JC, Thiebaud N, McGann JP, Komiyama T, Rothermel M, Neuromodulation in Chemosensory Pathways, Chem Senses 42(5) (2017) 375–379. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [71].Mandairon N, Linster C, Odor perception and olfactory bulb plasticity in adult mammals, J Neurophysiol 101(5) (2009) 2204–9. [DOI] [PubMed] [Google Scholar]
  • [72].Kass MD, Rosenthal MC, Pottackal J, McGann JP, Fear learning enhances neural responses to threat-predictive sensory stimuli, Science 342(6164) (2013) 1389–1392. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [73].Bhattarai JP, Schreck M, Moberly AH, Luo W, Ma M, Aversive Learning Increases Release Probability of Olfactory Sensory Neurons, Curr Biol 30(1) (2020) 31–41 e3. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [74].Ross JM, Fletcher ML, Learning-Dependent and -Independent Enhancement of Mitral/Tufted Cell Glomerular Odor Responses Following Olfactory Fear Conditioning in Awake Mice, J Neurosci 38(20) (2018) 4623–4640. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [75].Root CM, Denny CA, Hen R, Axel R, The participation of cortical amygdala in innate, odour-driven behaviour, Nature 515(7526) (2014) 269–73. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [76].Kondoh K, Lu Z, Ye X, Olson DP, Lowell BB, Buck LB, A specific area of olfactory cortex involved in stress hormone responses to predator odours, Nature 532(7597) (2016) 103–6. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [77].Kataoka N, Shima Y, Nakajima K, Nakamura K, A central master driver of psychosocial stress responses in the rat, Science 367(6482) (2020) 1105–1112. [DOI] [PubMed] [Google Scholar]
  • [78].Brennan PA, Kendrick KM, Mammalian social odours: attraction and individual recognition, Philosophical transactions of the Royal Society of London. Series B, Biological sciences 361(1476) (2006) 2061–78. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [79].Sanchez-Andrade G, Kendrick KM, The main olfactory system and social learning in mammals, Behav Brain Res 200(2) (2009) 323–35. [DOI] [PubMed] [Google Scholar]
  • [80].Spehr M, Kelliher KR, Li XH, Boehm T, Leinders-Zufall T, Zufall F, Essential role of the main olfactory system in social recognition of major histocompatibility complex peptide ligands, J Neurosci 26(7) (2006) 1961–70. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [81].Gadziola MA, Stetzik LA, Wright KN, Milton AJ, Arakawa K, Del Mar Cortijo M, Wesson DW, A Neural System that Represents the Association of Odors with Rewarded Outcomes and Promotes Behavioral Engagement, Cell Rep 32(3) (2020) 107919. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [82].Millman DJ, Murthy VN, Rapid Learning of Odor-Value Association in the Olfactory Striatum, J Neurosci 40(22) (2020) 4335–4347. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [83].Gadziola MA, Wesson DW, The Neural Representation of Goal-Directed Actions and Outcomes in the Ventral Striatum’s Olfactory Tubercle, J Neurosci 36(2) (2016) 548–60. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [84].Zhang Z, Liu Q, Wen P, Zhang J, Rao X, Zhou Z, Zhang H, He X, Li J, Zhou Z, Xu X, Zhang X, Luo R, Lv G, Li H, Cao P, Wang L, Xu F, Activation of the dopaminergic pathway from VTA to the medial olfactory tubercle generates odor-preference and reward, Elife 6 (2017). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [85].Choe HK, Reed MD, Benavidez N, Montgomery D, Soares N, Yim YS, Choi GB, Oxytocin Mediates Entrainment of Sensory Stimuli to Social Cues of Opposing Valence, Neuron 87(1) (2015) 152–63. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [86].Oettl LL, Ravi N, Schneider M, Scheller MF, Schneider P, Mitre M, da Silva Gouveia M, Froemke RC, Chao MV, Young WS, Meyer-Lindenberg A, Grinevich V, Shusterman R, Kelsch W, Oxytocin Enhances Social Recognition by Modulating Cortical Control of Early Olfactory Processing, Neuron 90(3) (2016) 609–21. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [87].Lee W, Hiura LC, Yang E, Broekman KA, Ophir AG, Curley JP, Social status in mouse social hierarchies is associated with variation in oxytocin and vasopressin 1a receptor densities, Horm Behav 114 (2019) 104551. [DOI] [PubMed] [Google Scholar]
  • [88].Wacker DW, Tobin VA, Noack J, Bishop VR, Duszkiewicz AJ, Engelmann M, Meddle SL, Ludwig M, Expression of early growth response protein 1 in vasopressin neurones of the rat anterior olfactory nucleus following social odour exposure, J Physiol 588(Pt 23) (2010) 4705–17. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [89].Aqrabawi AJ, Kim JC, Hippocampal projections to the anterior olfactory nucleus differentially convey spatiotemporal information during episodic odour memory, Nat Commun 9(1) (2018) 2735. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [90].Aqrabawi AJ, Browne CJ, Dargaei Z, Garand D, Khademullah CS, Woodin MA, Kim JC, Top-down modulation of olfactory-guided behaviours by the anterior olfactory nucleus pars medialis and ventral hippocampus, Nat Commun 7 (2016) 13721. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [91].Hoover WB, Vertes RP, Anatomical analysis of afferent projections to the medial prefrontal cortex in the rat, Brain Struct Funct 212(2) (2007) 149–79. [DOI] [PubMed] [Google Scholar]
  • [92].DeNardo LA, Berns DS, DeLoach K, Luo L, Connectivity of mouse somatosensory and prefrontal cortex examined with trans-synaptic tracing, Nature neuroscience 18(11) (2015) 1687–97. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [93].Ahrlund-Richter S, Xuan Y, van Lunteren JA, Kim H, Ortiz C, Pollak Dorocic I, Meletis K, Carlen M, A whole-brain atlas of monosynaptic input targeting four different cell types in the medial prefrontal cortex of the mouse, Nat Neurosci 22(4) (2019) 657–668. [DOI] [PubMed] [Google Scholar]
  • [94].Brunjes PC, The mouse olfactory peduncle. 2.The anterior limb of the anterior commissure, Front Neuroanat 6 (2012) 51. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [95].Biskamp J, Bartos M, Sauer JF, Organization of prefrontal network activity by respiration-related oscillations, Sci Rep 7 (2017) 45508. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [96].Moberly AH, Schreck M, Bhattarai JP, Zweifel LS, Luo W, Ma M, Olfactory inputs modulate respiration-related rhythmic activity in the prefrontal cortex and freezing behavior, Nat Commun 9(1) (2018) 1528. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [97].Gire DH, Franks KM, Zak JD, Tanaka KF, Whitesell JD, Mulligan AA, Hen R, Schoppa NE, Mitral cells in the olfactory bulb are mainly excited through a multistep signaling path, J Neurosci 32(9) (2012) 2964–75. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [98].Fukunaga I, Berning M, Kollo M, Schmaltz A, Schaefer AT, Two distinct channels of olfactory bulb output, Neuron 75(2) (2012) 320–9. [DOI] [PubMed] [Google Scholar]
  • [99].Phillips ME, Sachdev RN, Willhite DC, Shepherd GM, Respiration drives network activity and modulates synaptic and circuit processing of lateral inhibition in the olfactory bulb, J Neurosci 32(1) (2012) 85–98. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [100].Loureiro M, Achargui R, Flakowski J, Van Zessen R, Stefanelli T, Pascoli V, Luscher C, Social transmission of food safety depends on synaptic plasticity in the prefrontal cortex, Science 364(6444) (2019) 991–995. [DOI] [PubMed] [Google Scholar]
  • [101].Zhong W, Ciatipis M, Wolfenstetter T, Jessberger J, Muller C, Ponsel S, Yanovsky Y, Brankack J, Tort ABL, Draguhn A, Selective entrainment of gamma subbands by different slow network oscillations, Proc Natl Acad Sci U S A 114(17) (2017) 4519–4524. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [102].Bagur S, Lefort JM, Lacroix MM, de Lavilleon G, Herry C, Billand C, Geoffroy H, Benchenane K, Dissociation of fear initiation and maintenance by breathing-driven prefrontal oscillations, bioRxiv (2018) doi: 10.1101/468264. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [103].Karalis N, Sirota A, Breathing coordinates limbic network dynamics underlying memory consolidation, Sneak Peek Cell Press Under Review (Neuron) (2018) SSRN 3283711, 2018. [Google Scholar]
  • [104].Del Negro CA, Funk GD, Feldman JL, Breathing matters, Nat Rev Neurosci 19(6) (2018) 351–367. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [105].Wachowiak M, All in a sniff: olfaction as a model for active sensing, Neuron 71(6) (2011) 962–73. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [106].Wesson DW, Donahou TN, Johnson MO, Wachowiak M, Sniffing behavior of mice during performance in odor-guided tasks, Chem Senses 33(7) (2008) 581–96. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [107].Wesson DW, Sniffing behavior communicates social hierarchy, Curr Biol 23(7) (2013) 575–80. [DOI] [PubMed] [Google Scholar]
  • [108].Brouillard C, Carrive P, Camus F, Benoliel JJ, Similowski T, Sevoz-Couche C, Long-lasting bradypnea induced by repeated social defeat, Am J Physiol Regul Integr Comp Physiol 311(2) (2016) R352–64. [DOI] [PubMed] [Google Scholar]
  • [109].Sullivan RM, Wilson DA, Ravel N, Mouly AM, Olfactory memory networks: from emotional learning to social behaviors, Front Behav Neurosci 9 (2015) 36. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [110].Kontaris I, East BS, Wilson DA, Behavioral and Neurobiological Convergence of Odor, Mood and Emotion: A Review, Front Behav Neurosci 14 (2020) 35. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [111].Heck DH, Kozma R, Kay LM, The rhythm of memory: how breathing shapes memory function, J Neurophysiol 122(2) (2019) 563–571. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [112].Merrick C, Godwin CA, Geisler MW, Morsella E, The olfactory system as the gateway to the neural correlates of consciousness, Front Psychol 4 (2014) 1011. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [113].Price JL, Comparative aspects of amygdala connectivity, Ann N Y Acad Sci 985 (2003) 50–8. [DOI] [PubMed] [Google Scholar]
  • [114].Linster C, Cleland TA, Neuromodulation of olfactory transformations, Curr Opin Neurobiol 40 (2016) 170–177. [DOI] [PubMed] [Google Scholar]
  • [115].McCormick DA, Nestvogel DB, He BJ, Neuromodulation of Brain State and Behavior, Annu Rev Neurosci 43 (2020) 391–415. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [116].Li Y, Zhong W, Wang D, Feng Q, Liu Z, Zhou J, Jia C, Hu F, Zeng J, Guo Q, Fu L, Luo M, Serotonin neurons in the dorsal raphe nucleus encode reward signals, Nat Commun 7 (2016) 10503. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [117].Varela F, Lachaux JP, Rodriguez E, Martinerie J, The brainweb: phase synchronization and large-scale integration, Nature reviews. Neuroscience 2(4) (2001) 229–39. [DOI] [PubMed] [Google Scholar]
  • [118].Harris AZ, Gordon JA, Long-range neural synchrony in behavior, Annu Rev Neurosci 38 (2015) 171–94. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [119].Kingsbury L, Huang S, Wang J, Gu K, Golshani P, Wu YE, Hong W, Correlated Neural Activity and Encoding of Behavior across Brains of Socially Interacting Animals, Cell 178(2) (2019) 429–446 e16. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [120].Javitt DC, Sensory processing in schizophrenia: neither simple nor intact, Schizophr Bull 35(6) (2009) 1059–64. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [121].Insausti R, Marcos P, Arroyo-Jimenez MM, Blaizot X, Martinez-Marcos A, Comparative aspects of the olfactory portion of the entorhinal cortex and its projection to the hippocampus in rodents, nonhuman primates, and the human brain, Brain Res Bull 57(3–4) (2002) 557–60. [DOI] [PubMed] [Google Scholar]
  • [122].Goncalves Pereira PM, Insausti R, Artacho-Perula E, Salmenpera T, Kalviainen R, Pitkanen A, MR volumetric analysis of the piriform cortex and cortical amygdala in drug-refractory temporal lobe epilepsy, AJNR Am J Neuroradiol 26(2) (2005) 319–32. [PMC free article] [PubMed] [Google Scholar]
  • [123].Eslinger PJ, Damasio AR, Van Hoesen GW, Olfactory dysfunction in man: anatomical and behavioral aspects, Brain Cogn 1(3) (1982) 259–85. [DOI] [PubMed] [Google Scholar]
  • [124].Howard JD, Plailly J, Grueschow M, Haynes JD, Gottfried JA, Odor quality coding and categorization in human posterior piriform cortex, Nat Neurosci 12(7) (2009) 932–8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [125].Zelano C, Bensafi M, Porter J, Mainland J, Johnson B, Bremner E, Telles C, Khan R, Sobel N, Attentional modulation in human primary olfactory cortex, Nat Neurosci 8(1) (2005) 114–20. [DOI] [PubMed] [Google Scholar]
  • [126].Milardi D, Cacciola A, Calamuneri A, Ghilardi MF, Caminiti F, Cascio F, Andronaco V, Anastasi G, Mormina E, Arrigo A, Bruschetta D, Quartarone A, The Olfactory System Revealed: Non-Invasive Mapping by using Constrained Spherical Deconvolution Tractography in Healthy Humans, Front Neuroanat 11 (2017) 32. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [127].Gottfried JA, Zald DH, On the scent of human olfactory orbitofrontal cortex: meta-analysis and comparison to non-human primates, Brain Res Brain Res Rev 50(2) (2005) 287–304. [DOI] [PubMed] [Google Scholar]
  • [128].Sobel N, Prabhakaran V, Desmond JE, Glover GH, Goode RL, Sullivan EV, Gabrieli JD, Sniffing and smelling: separate subsystems in the human olfactory cortex, Nature 392(6673) (1998) 282–6. [DOI] [PubMed] [Google Scholar]
  • [129].Seubert J, Freiherr J, Frasnelli J, Hummel T, Lundstrom JN, Orbitofrontal cortex and olfactory bulb volume predict distinct aspects of olfactory performance in healthy subjects, Cereb Cortex 23(10) (2013) 2448–56. [DOI] [PubMed] [Google Scholar]
  • [130].Zhou G, Lane G, Cooper SL, Kahnt T, Zelano C, Characterizing functional pathways of the human olfactory system, Elife 8 (2019). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [131].Zelano C, Jiang H, Zhou G, Arora N, Schuele S, Rosenow J, Gottfried JA, Nasal Respiration Entrains Human Limbic Oscillations and Modulates Cognitive Function, J Neurosci 36(49) (2016) 12448–12467. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [132].Herrero JL, Khuvis S, Yeagle E, Cerf M, Mehta AD, Breathing above the brain stem: volitional control and attentional modulation in humans, J Neurophysiol 119(1) (2018) 145–159. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [133].Fagundo AB, Jimenez-Murcia S, Giner-Bartolome C, Islam MA, de la Torre R, Pastor A, Casanueva FF, Crujeiras AB, Granero R, Banos R, Botella C, Fernandez-Real JM, Fruhbeck G, Gomez-Ambrosi J, Menchon JM, Tinahones FJ, Fernandez-Aranda F, Modulation of Higher-Order Olfaction Components on Executive Functions in Humans, PLoS One 10(6) (2015) e0130319. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [134].Hedner M, Larsson M, Arnold N, Zucco GM, Hummel T, Cognitive factors in odor detection, odor discrimination, and odor identification tasks, J Clin Exp Neuropsychol 32(10) (2010) 1062–7. [DOI] [PubMed] [Google Scholar]
  • [135].Herman AM, Critchley H, Duka T, Decreased olfactory discrimination is associated with impulsivity in healthy volunteers, Sci Rep 8(1) (2018) 15584. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [136].Westervelt HJ, Ruffolo JS, Tremont G, Assessing olfaction in the neuropsychological exam: the relationship between odor identification and cognition in older adults, Arch Clin Neuropsychol 20(6) (2005) 761–9. [DOI] [PubMed] [Google Scholar]
  • [137].Boesveldt S, Yee JR, McClintock MK, Lundstrom JN, Olfactory function and the social lives of older adults: a matter of sex, Sci Rep 7 (2017) 45118. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [138].Gaby JM, Zayas V, Smelling is Telling: Human Olfactory Cues Influence Social Judgments in Semi-Realistic Interactions, Chem Senses 42(5) (2017) 405–418. [DOI] [PubMed] [Google Scholar]
  • [139].Kastner AK, Flohr EL, Pauli P, Wieser MJ, A Scent of Anxiety: Olfactory Context Conditioning and its Influence on Social Cues, Chem Senses 41(2) (2016) 143–53. [DOI] [PubMed] [Google Scholar]
  • [140].Leschak CJ, Eisenberger NI, The role of social relationships in the link between olfactory dysfunction and mortality, PLoS One 13(5) (2018) e0196708. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [141].Xu L, Liu J, Wroblewski KE, McClintock MK, Pinto JM, Odor Sensitivity Versus Odor Identification in Older US Adults: Associations With Cognition, Age, Gender, and Race, Chem Senses 45(4) (2020) 321–330. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [142].Zou LQ, Yang ZY, Wang Y, Lui SS, Chen AT, Cheung EF, Chan RC, What does the nose know? Olfactory function predicts social network size in human, Sci Rep 6 (2016) 25026. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [143].Liu X, Liu S, Huang R, Chen X, Xie Y, Ma R, Luo Y, Bu J, Zhang X, Neuroimaging Studies Reveal the Subtle Difference Among Social Network Size Measurements and Shed Light on New Directions, Front Neurosci 12 (2018) 461. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [144].Rolls ET, Kringelbach ML, de Araujo IE, Different representations of pleasant and unpleasant odours in the human brain, Eur J Neurosci 18(3) (2003) 695–703. [DOI] [PubMed] [Google Scholar]
  • [145].de Nijs J, Meijer JH, de Haan L, Meijer CJ, Bruggeman R, van Haren NEM, Kahn RS, Cahn W, Associations between olfactory identification and (social) cognitive functioning: A cross-sectional study in schizophrenia patients and healthy controls, Psychiatry Res 266 (2018) 147–151. [DOI] [PubMed] [Google Scholar]
  • [146].Kohler CG, Barrett FS, Gur RC, Turetsky BI, Moberg PJ, Association between facial emotion recognition and odor identification in schizophrenia, J Neuropsychiatry Clin Neurosci 19(2) (2007) 128–31. [DOI] [PubMed] [Google Scholar]
  • [147].Mossaheb N, Kaufmann RM, Schlogelhofer M, Aninilkumparambil T, Himmelbauer C, Gold A, Zehetmayer S, Hoffmann H, Traue HC, Aschauer H, The Impact of Sex Differences on Odor Identification and Facial Affect Recognition in Patients with Schizophrenia Spectrum Disorders, Front Psychiatry 9 (2018) 9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [148].Lahera G, Ruiz-Murugarren S, Fernandez-Liria A, Saiz-Ruiz J, Buck BE, Penn DL, Relationship between olfactory function and social cognition in euthymic bipolar patients, CNS Spectr 21(1) (2016) 53–9. [DOI] [PubMed] [Google Scholar]
  • [149].Cumming AG, Matthews NL, Park S, Olfactory identification and preference in bipolar disorder and schizophrenia, Eur Arch Psychiatry Clin Neurosci 261(4) (2011) 251–9. [DOI] [PubMed] [Google Scholar]
  • [150].Hardy C, Rosedale M, Messinger JW, Kleinhaus K, Aujero N, Silva H, Goetz RR, Goetz D, Harkavy-Friedman J, Malaspina D, Olfactory acuity is associated with mood and function in a pilot study of stable bipolar disorder patients, Bipolar Disord 14(1) (2012) 109–17. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [151].Thye MD, Bednarz HM, Herringshaw AJ, Sartin EB, Kana RK, The impact of atypical sensory processing on social impairments in autism spectrum disorder, Dev Cogn Neurosci 29 (2018) 151–167. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [152].Huang TN, Yen TL, Qiu LR, Chuang HC, Lerch JP, Hsueh YP, Haploinsufficiency of autism causative gene Tbr1 impairs olfactory discrimination and neuronal activation of the olfactory system in mice, Mol Autism 10 (2019) 5. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [153].Liu X, Zhou Y, Li S, Yang D, Jiao M, Liu X, Wang Z, Type 3 adenylyl cyclase in the main olfactory epithelium participates in depression-like and anxiety-like behaviours, J Affect Disord 268 (2020) 28–38. [DOI] [PubMed] [Google Scholar]
  • [154].Cryan JF, Mombereau C, In search of a depressed mouse: utility of models for studying depression-related behavior in genetically modified mice, Mol Psychiatry 9(4) (2004) 326–57. [DOI] [PubMed] [Google Scholar]
  • [155].Lucas G, Rymar VV, Du J, Mnie-Filali O, Bisgaard C, Manta S, Lambas-Senas L, Wiborg O, Haddjeri N, Pineyro G, Sadikot AF, Debonnel G, Serotonin(4) (5-HT(4)) receptor agonists are putative antidepressants with a rapid onset of action, Neuron 55(5) (2007) 712–25. [DOI] [PubMed] [Google Scholar]
  • [156].Murugan M, Jang HJ, Park M, Miller EM, Cox J, Taliaferro JP, Parker NF, Bhave V, Hur H, Liang Y, Nectow AR, Pillow JW, Witten IB, Combined Social and Spatial Coding in a Descending Projection from the Prefrontal Cortex, Cell 171(7) (2017) 1663–1677 e16. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [157].Lein ES, Hawrylycz MJ, Ao N, Ayres M, Bensinger A, Bernard A, Boe AF, Boguski MS, Brockway KS, Byrnes EJ, Chen L, Chen L, Chen TM, Chin MC, Chong J, Crook BE, Czaplinska A, Dang CN, Datta S, Dee NR, Desaki AL, Desta T, Diep E, Dolbeare TA, Donelan MJ, Dong HW, Dougherty JG, Duncan BJ, Ebbert AJ, Eichele G, Estin LK, Faber C, Facer BA, Fields R, Fischer SR, Fliss TP, Frensley C, Gates SN, Glattfelder KJ, Halverson KR, Hart MR, Hohmann JG, Howell MP, Jeung DP, Johnson RA, Karr PT, Kawal R, Kidney JM, Knapik RH, Kuan CL, Lake JH, Laramee AR, Larsen KD, Lau C, Lemon TA, Liang AJ, Liu Y, Luong LT, Michaels J, Morgan JJ, Morgan RJ, Mortrud MT, Mosqueda NF, Ng LL, Ng R, Orta GJ, Overly CC, Pak TH, Parry SE, Pathak SD, Pearson OC, Puchalski RB, Riley ZL, Rockett HR, Rowland SA, Royall JJ, Ruiz MJ, Sarno NR, Schaffnit K, Shapovalova NV, Sivisay T, Slaughterbeck CR, Smith SC, Smith KA, Smith BI, Sodt AJ, Stewart NN, Stumpf KR, Sunkin SM, Sutram M, Tam A, Teemer CD, Thaller C, Thompson CL, Varnam LR, Visel A, Whitlock RM, Wohnoutka PE, Wolkey CK, Wong VY, Wood M, Yaylaoglu MB, Young RC, Youngstrom BL, Yuan XF, Zhang B, Zwingman TA, Jones AR, Genome-wide atlas of gene expression in the adult mouse brain, Nature 445(7124) (2007) 168–76. [DOI] [PubMed] [Google Scholar]
  • [158].Majka P, Kublik E, Furga G, Wojcik DK, Common atlas format and 3D brain atlas reconstructor: infrastructure for constructing 3D brain atlases, Neuroinformatics 10(2) (2012) 181–97. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [159].Fan L, Li H, Zhuo J, Zhang Y, Wang J, Chen L, Yang Z, Chu C, Xie S, Laird AR, Fox PT, Eickhoff SB, Yu C, Jiang T, The Human Brainnetome Atlas: A New Brain Atlas Based on Connectional Architecture, Cereb Cortex 26(8) (2016) 3508–26. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [160].Bakker R, Tiesinga P, Kotter R, The Scalable Brain Atlas: Instant Web-Based Access to Public Brain Atlases and Related Content, Neuroinformatics 13(3) (2015) 353–66. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [161].Lopez-Elizalde R, Campero A, Sanchez-Delgadillo T, Lemus-Rodriguez Y, Lopez-Gonzalez MI, Godinez-Rubi M, Anatomy of the olfactory nerve: A comprehensive review with cadaveric dissection, Clin Anat 31(1) (2018) 109–117. [DOI] [PubMed] [Google Scholar]
  • [162].Mai JK, Majtanik M, Paxinos G, Atlas of the Human Brain, 4th edition, Academic Press; (2015). [Google Scholar]

RESOURCES