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. 2024 Aug 3;229(9):2327–2338. doi: 10.1007/s00429-024-02837-w

From emotional arousal to executive action. Role of the prefrontal cortex

Stefan M Brudzynski 1,✉, Jeffrey S Burgdorf 2, Joseph R Moskal 2
PMCID: PMC11611949  PMID: 39096390

Abstract

Emotional arousal is caused by the activity of two parallel ascending systems targeting mostly the subcortical limbic regions and the prefrontal cortex. The aversive, negative arousal system is initiated by the activity of the mesolimbic cholinergic system and the hedonic, appetitive, arousal is initiated by the activity of the mesolimbic dopaminergic system. Both ascending projections have a diffused nature and arise from the rostral, tegmental part of the brain reticular activating system. The mesolimbic cholinergic system originates in the laterodorsal tegmental nucleus and the mesolimbic dopaminergic system in the ventral tegmental area. Cholinergic and dopaminergic arousal systems have converging input to the medial prefrontal cortex. The arousal system can modulate cortical EEG with alpha rhythms, which enhance synaptic strength as shown by an increase in long-term potentiation (LTP), whereas delta frequencies are associated with decreased arousal and a decrease in synaptic strength as shown by an increase in long-term depotentiation (LTD). It is postulated that the medial prefrontal cortex is an adaptable node with decision making capability and may control the switch between positive and negative affect and is responsible for modifying or changing emotional state and its expression.

Keywords: Emotion, Affect, Arousal, Ultrasonic vocalization, Vocal expression of emotion, Medial prefrontal cortex, Dopamine, Acetylcholine, Cortical oscillations

Introduction

There is a growing body of data that are helping to explain the brain mechanisms of emotional arousal, but relatively little evidence is available to explain how this arousal is initiated and how it is transformed into behavioral responses. In this review, we have summarized studies on ultrasonic vocalizations emitted by rats during both processes, i.e., during initiation and development of emotional arousal and during postulated decision making by the prefrontal cortex in response to this arousal. The choice of rat ultrasonic vocalization is the best approach in studies of emotionality since vocalizations of adult rats were shown to express the magnitude of this arousal and its valence (Knutson et al. 2002; Brudzynski 2007; 2021; Burgdorf et al. 2020). Ultrasonic vocalizations emitted by rodents have been continuously studied since their discovery in 1954 (Anderson 1954), adding important insights to our current understanding of their acoustic structure, numerous biological functions, development, pharmacology, and mechanisms of their initiation by the emotional arousal circuits (Brudzynski 2021).

In a nutshell, emotional arousal evolved as an adaptive mechanism with a crucial survival role for the organism. Emotional arousal is a brain mechanism that brings the organism’s attention to salient stimuli and situations (stimulus selection). The modulation of emotional arousal is also important for the organism, and is affecting (1) intensity of arousal, (2) prolonging attention to these stimuli and cues (duration of arousal), (3) categorizing them as beneficial, needed, and appetitive (positive arousal) or harmful, undesirable, dangerous (negative arousal), (4) as well as forcing the organism to act (subjective feelings).

Although emotional states were well understood and physiologically characterized in 1920s (Cannon 1927; Bard 1928), the process of emotional arousal was unclear. It was argued that the reticulothalamocortical projections together with the limbic system are responsible for a mixed alerting state, attention, vigilance, and emotional-motivational arousal (Lindsley 1970). Emotional arousal was initially suggested as part of a general unidimensional continuum of arousal, which begins with low arousal as in sleepiness to high arousal as in emotional behavior (Duffy 1934; 1957). Consequently, the term “emotional arousal” has been postulated to be unnecessary (Johnston and Vitello 2021). Discovery of a general cognitive, cortical arousal by the ascending reticular system (Moruzzi and Magoun 1949) has demonstrated that cognitive and emotional arousal represent two different, although interacting physiological processes and states. Subsequently, two arousal systems were postulated, one for general cortical arousal originating from activity of the reticular activating system and the other for emotional arousal originating from an overall activity of the limbic system (Routtenberg 1968). Nevertheless, the neurophysiological mechanisms of emotional arousal and control of its valence remained unclear and mostly unknown.

Research during the last 20 years, which utilized rat ultrasonic vocalizations as indices of emotionality, has demonstrated distinct emotional arousal systems originating from portions of the upper reticular activating system in parallel to the ascending cognitive arousal system. This parallel emotional arousal system targets mostly subcortical limbic structures and the prefrontal cortex and consists of two neurochemically coded and functionally opposite components for appetitive or aversive arousal (Brudzynski 2013; 2014; 2021). The present review will discuss the initiation mechanisms for positive or negative arousal as compared to cognitive arousal, and the main neurotransmitters involved. It will also explain the physiological functions of the emotional arousal systems from brain stem to the frontal cortex, as well as integrative cortical mechanisms leading to the analysis and decision making for behavioral output.

General (cognitive) arousal system

The reticular formation is the most ancient part of the brain, constitutes the reticular core of the brain stem and is critically important for a variety of normal brain functions (Scheibel 1987). The reticular core was also termed the “isodendritic core” of the brain stem. This is because of the morphology of the neurons with overlapping dendritic fields, which process incoming afferent information of very heterogenous origin (Ramón-Moliner and Nauta 1966). All incoming stimuli to the brain have connections with the reticular formation, a critical part of the reticular activating system. The incoming sensory afferents send numerous converging collaterals to the brain stem reticular system from specific pathways of all modalities including somatic and visceral inputs (Brodal 1949; Starzl et al. 1951a, b; Nauta and Kuypers 1958; Lindsley 1961). In turn, the reticular system sends long ascending projections to the thalamic intralaminar and midline nuclei as well as the neocortex and descending pathways to the spinal cord (Starzl et al. 1951a, b; Steriade et al. 1980). The ascending projections arise from the rostral parts of the reticular system at the mesencephalic, anterior, and mid-pontine levels, while the descending pathways originate from the caudal pontine and the medullary reticular formation (Jones and Yang 1985; Jones 2003; 2011; Jang and Kwon 2015a). The ascending projections, called nonspecific, are distinct from the specific sensory afferent pathways (Starzl et al. 1951a, b). The thalamic relay nuclei send diffuse projections widely distributed in the neocortex (Lindsley 1961). However, a portion of the ascending reticular fibres reaches the cortex directly (Lindsley 1961; Jang and Kwon 2015b; Newman and Liu 1987).

The ascending projections to the forebrain follow two pathways forming a dorsal and ventral leaf. The dorsal pathway enters the thalamic nonspecific relay nuclei, while the ventral, extra-thalamic pathway projects through the subthalamus, hypothalamus, septum, and basal forebrain (Scheibel 1987; Jones 2003). Approximately 10% of the ventral projections continue directly to the frontal lobe with the greatest concentration of terminals in the frontal cortex (Scheibel 1987). Human brain tractographic analyses using diffusion tensor imaging, have shown that the reticular activating system has 2–3 times more connections to the prefrontal cortex, particularly lateral and ventromedial prefrontal cortices, than to the remaining neocortical regions (Jang and Kwon 2015b).

The dorsal pathway of the ascending reticular projections that goes through the thalamus (reticulothalamocortical pathway) seems to be a more recent evolutionary development, while the ventral pathways (direct and indirect), associated with olfactory functions (rhinencephalon), are phylogenetically older (Kaas 2009). Thus, the ventral pathways through the basal forebrain might be more important for maintaining cortical arousal in the rat brain than in the human brain (Fuller et al. 2011). The ventral pathway also has two relay structures, namely the nucleus basalis, and the posterior hypothalamus. Both send further direct projections to the cortex (Jones and Mühlethaler 1999; Lin et al. 2011). Neurons of these structures have some functional and morphological similarities to neurons of the reticular formation (Jones 2003; Miyawaki et al. 2023).

The ascending reticulocortical and reticulothalamocortical projections from the reticular activating system influence the entire cortex and were shown to selectively activate or suppress cortical metabolic activity as studied by 2-deoxuglucose method (Gonzalez-Lima and Scheich 1985). They are responsible for the regulation and maintenance of the awake state, which is characterized by consciousness, general arousal, attention, the ability to respond to external stimuli, vigilance, and awareness (van Schie et al 2021). Although the arriving afferent impulses enhance arousal and attention, the reticular activating system can maintain wakefulness by an intrinsic and autonomous mechanism in the absence of external stimuli and even with lesions of sensory pathways (Lindsley et al. 1950). Conversely, damaging the ascending projections of the reticular system causes a comatose state, as has been shown in the cat and macaque (Lindsley et al. 1949; Magoun 1952). It has been confirmed using positron emission tomography, that the ascending reticular activating system and thalamic intralaminary nuclei, also known as the reticulothalamocortical pathway, are active in the human brain during attention-demanding tasks (Kinomura et al. 1996). Diffusion tensor tomography studies in patients with impaired consciousness caused by internal brain hemorrhage have also confirmed that injury and thinning of the lower dorsal ascending reticular activating system was associated with impaired consciousness and alertness (Jang et al. 2019).

Neurotransmitters of the reticular activating system

The ascending reticular activating system arises from many nuclei, including those embedded within the reticular formation and those outside of the formation. Retrograde neuronal labeling using fast blue or horseradish peroxidase-wheat germ agglutinin conjugate in rats revealed at least 33 distinct nuclei or subnuclear divisions within the brain stem reticular formation that project directly to the neocortex (Newman and Liu 1987). These direct corticopetal pathways are mostly glutamatergic and a smaller portion of them are GABAergic (Jones and Mühlethaler 1999; Jones 2003). There are many aminergic cell groups that belong to the reticular system; (1) raphe neurons producing serotonin that widely project to diencephalon and forebrain; (2) catecholaminergic neurons producing norepinephrine or dopamine with a high concentration of dopaminergic neurons in the substantia nigra and the ventral tegmental area which project to the limbic system; and (3) neurons of the locus coeruleus with a high concentration of norepinephrinergic neurons that project through the entire encephalon (Scheibel 1987). The reticular activating system also includes cholinergic neurons with ascending projections originating from the laterodorsal tegmental nucleus, the basal forebrain, and partially from the pedunculopontine tegmental nucleus. Cholinergic projections from the basal forebrain originate mostly from the nucleus basalis, which acts as another relay station for the ascending input from the brain stem reticular activating system that forms the reticulobasalocortical pathway (Reiner and Vincent 1987; Jones and Mühlethaler 1999; Mesulam et al. 1983; 1989).

Another relay center is the posterior hypothalamus with histaminergic neurons located in the tuberomammillary nucleus and posterior hypothalamus that have widespread projections to the entire brain (Lin 2000; Arrigoni and Fuller 2022; Lin et al. 2023). The histaminergic neurons along with neuropeptide neurotransmitters (e.g., galanin, enkephalins, substance P) are involved in the maintenance of the waking state and cortical activation (Lin et al. 2011) mostly by the activation of cholinergic neurons in the basal forebrain (Zant et al. 2012). Activity of the tuberomammillary histaminergic neurons is modulated by glutamate, GABA, monoaminergic, cholinergic, and peptidergic terminals. In turn, histamine, through direct interaction at the varicosities, may suppress release of various neurotransmitters (e.g., glutamate, acetylcholine, norepinephrine, dopamine, serotonin, and GABA; Lin et al. 2011; Ma et al 2018). Additionally, many neurons involved in the maintenance of arousal and consciousness have dual transmitter system co-releasing two transmitters; for example, histamine and GABA, acetylcholine and GABA, glutamate and orexin, GABA, and relaxin-3 (Ma et al. 2018). Co-release of acetylcholine and GABA in the pedunculopontine nucleus has been proposed (Jia et al. 2003). The neuropeptide relaxin-3 is the newest addition to the family of arousal-modulating peptides and is predominantly produced in the brain stem nucleus incertus (Ma et al. 2017). Finally, nitric oxide, one of the signalling molecules typically associated with cholinergic neurons also has been postulated to be a regulator of the activity of the ascending reticular activating system (Vincent 2000). Furthermore, it has been shown that cholinergic axons arriving from laterodorsal tegmental nucleus to the thalamus release nitric oxide (Miyazaki et al. 1996).

This multitude of ascending arousal pathways with different neurochemical properties clearly indicates that arousal is a complex process with many functional components (Jones 2011). That there are numerous neurotransmitter and neuromodulator systems involved in the arousal process may suggest the existence of multiple arousal systems which jointly contribute to general arousal (Berlucchi 1997), but this remains to be determined. It has also been suggested that there are three arousal systems carried out by noradrenergic, dopaminergic, and serotonergic projections in various combinations, and that they are related to orientation, integration, and energetic aspects of behavior (Trofimova and Robbins 2016). But the question remains as to which parts of this complex arousal mechanism are devoted to emotional arousal versus cognitive arousal.

Emotional arousal system for aversive/negative state

Neuropharmacological studies modulating 22 kHz ultrasonic vocalizations in rats have revealed that the aversive arousal and maintenance of the aversive state is induced by the activity of the ascending mesolimbic cholinergic system with projections originating from the laterodorsal tegmental nucleus (Brudzynski 1994; Brudzynski 2010; 2014). Twenty-two kHz vocalizations signal negative internal states akin to anxiety (but not fear) and dysphoric states (Jelen et al. 2003; Simola 2015). They have been proposed to represent evolutionary equivalent of human crying (Brudzynski 2019).

The ascending mesolimbic cholinergic reticular system was first identified in 1967 (Shute and Lewis 1967). This system targets predominantly the subcortical limbic and related structures that reach the frontal cortex; these include the midline thalamic nuclei, hypothalamus, basal forebrain areas, septum (Satoh and Fibiger 1986; Fibiger and Vincent 1987; Woolf et al. 1990; Semba and Fibiger 1992). These afferents are direct connections to the target structures as evidenced by the fluorescent retrograde tracer, fluorogold, injected into the lateral septum, which labelled identified cholinergic neurons in the laterodorsal tegmental nucleus (Bihari et al. 2003). Twenty-two kHz vocalizations can be induced by direct cholinergic activation from all these target structures, apart from the cortex, by carbachol (Brudzynski 1994). This system is well preserved in evolution and cholinergic activation of a homolog system in the cat’s brain also induced aversive anxiety-type responses with concurrent robust emission of defensive growling vocalizations (Myers 1964; Várszegi and Decsi 1967; Brudzynski 1981; Brudzynski et al. 1993).

Intracerebral injections of carbachol, in addition to local action, trigger limbic loops between the injected site and the laterodorsal tegmental nucleus (limbic midbrain area, Nauta 1958) and in this way activate the cholinergic neurons of the ascending mesolimbic system that develop and augment the aversive state (Brudzynski et al. 2011a, b). The aversive emotional arousal system is a diffuse and extensive system. Its activity can be pharmacologically initiated from most of the locations innervated by that system, and it quickly develops into a fully blown emotional state (Brudzynski 2010, 2007; Brudzynski et al. 2011a, 2011b). Development of this general emotional state is likely due to electric coupling of laterodorsal tegmental neurons, a phenomenon that has been shown for some nuclei of the reticular activating system (Garcia-Rill et al. 2013). Electrical coupling via gap junctions allows activation of the system in its entirety and allows synchronous firing, allowing for more persistent brain rhythms. The cholinergic neurons of the laterodorsal tegmental nucleus are always active during aversive arousal, are responding with phasic excitation by noxious stimuli, such as tail pinch (Kayama et al. 1991), and were also shown to enhance the startle response (Azzopardi et al. 2018).

Direct stimulation of the laterodorsal tegmental nucleus, which is the primary source of the ascending mesolimbic cholinergic system, can also induce aversive states. Thus, direct intracerebral stimulation of the laterodorsal tegmental nucleus by glutamate activated cholinergic neurons and induced comparable 22 kHz vocalizations and other aversive behaviors. These could be antagonized by atropine or scopolamine given to target areas such as the hypothalamus or the lateral septum (Brudzynski and Barnabi 1996; Bihari et al. 2003).

Large numbers of cholinergic neurons are accumulated within or in the immediate vicinity of the laterodorsal tegmental nucleus, although these neurons do not constitute most neurons in this nucleus (Vincent et al. 1983; Kubota et al. 1992; Manaye et al. 1999; Wang and Morales 2009). Some neurons of the laterodorsal tegmental nucleus are spontaneously active at low rates (0.2–5 Hz) (Kayama et al. 1991) suggesting maintenance of some constant tonus in the mesolimbic cholinergic system. The cholinergic neurons with extensive dendritic arborizations send myelinated branching axons to other distant targets and not to local circuits (Kubota et al. 1992). This axonal branching is an also characteristic of the ascending cholinergic projections from the basal nucleus. As studied in mice, individual axonal arbors showed more than 1000 branching points and had total axon lengths up to 50 cm (Wu et al. 2014). These long and branching ascending axons have high numbers of varicosities with some synaptic contacts (Arvidsson et al. 1997; Tsutsumi et al. 2007; Parent and Descarries 2008). They may influence extensive areas of the limbic system (Nieuwenhuys 1996). This mode of neurotransmission raises the possibility of volume transmission, as opposed to wire transmission (Agnati et al. 2006). This mode of transmission, for phasic acetylcholine release in the cortex, has also been postulated as the underlying mechanism for the cholinergic innervation originating from its source in the basal forebrain (Sarter et al. 2009).

Cholinergic inputs in rat cortex demonstrated that the highest density of cholinergic axons and varicosities is found in the frontal cortex, with the number of varicosities reaching 5.4 × 106/mm3 (Mechawar et al. 2000).

Emotional arousal system for appetitive/hedonic state

Neuropharmacological studies recording 50 kHz ultrasonic vocalizations in rats demonstrated that the positive, appetitive state is induced by the activity of the ascending mesolimbic dopaminergic system originating from the ventral tegmental area (Knutson et al. 1999; Winting and Brudzynski 2001; Burgdorf et al. 2000; 2001; 2007; Thompson et al. 2006; Brudzynski et al 2011a, b; Brudzynski 2013; Pereira et al. 2014). Fifty kHz vocalizations signal a positive, hedonic affective state akin to joy, pleasure, euphoric state, or the expectation of such states (Burgdorf et al. 2000; 2011; Simola 2015; Simola and Brudzynski 2018; Simola and Granon 2019). Hedonic state is expressed predominantly by frequency- modulated 50 kHz vocalizations (Burgdorf et al. 2011), and emission of these calls is proportional to the intensity of the positive state (Hinchcliffe et al. 2020). Prolonged emission of 50 kHz vocalizations has been proposed as the ancestral equivalent of human laughter, particularly human childhood laughter and social joy (Panksepp and Burgdorf 2000; 2003; Panksepp 2007).

The literature on the mesolimbic dopaminergic system is particularly extensive in relation to reward, reinforcement, and motivated behaviors [see Ikemoto (2007), where an “action-arousal” function of the mesolimbic system has been discussed]. This review pertains predominantly to the affective neuroethological concept of behavioral activating properties of dopaminergic neurons and their role in emotional arousal (Alcaro et al. 2007).

The term “meso-limbic dopamine system” was suggested for the first time in 1970 (Fuxe et al 1970; Ungerstedt 1971) and originates in the ventral tegmental area (A10 group of neurons) (Björklund and Lindvall 1978; 1984; Fallon and Moore 1978a, 1978b). The ascending connections of the mesolimbic dopaminergic system have extensive intradiencephalic projections and target basal forebrain areas and ventral striatum, ventral pallidum, olfactory tubercle, olfactory bulb, nucleus accumbens, as well as hypothalamus, preoptic area, bed nucleus of stria terminalis, lateral septum, and limbic cortices as entorhinal and piriform cortex and prefrontal cortex (Björklund and Lindvall 1978; 1984; Fallon and Moore 1978a, b; Ikemoto 2007; Alcaro et al. 2007; Morales and Margolis 2017; Cornwall et al. 1990).

Intracerebral application of D-amphetamine, a dopamine releaser, induced 50 kHz vocalizations in rats from most of these structures (Brudzynski et al. 2011a, b; Burgdorf et al. 2001; 2007; Thompson et al. 2006; Silkstone et al. 2016). Dopamine-dependent 50 kHz calls were also induced from the anterior hypothalamic-preoptic area by glutamate and were antagonized by haloperidol confirming their dopaminergic nature (Wintink and Brudzynski 2001). This elaborate system resembles and overlaps with the regions innervated by the mesolimbic cholinergic system, described above. The exact cellular mechanism of the initiation of the appetitive state and vocalizations is not known, but it may be dependent on the loops between the ventral striatum and the ventral tegmental areas. Such loops have been recently identified using retrograde and anterograde tracers and electrophysiological methods (Wouterlood et al. 2018).

The ascending dopaminergic system appeared very early in evolution serving initially for control of movement and is probably present in all vertebrates as the nigrostriatal pathway. However, the mesolimbic and mesocortical pathways evolved later in terrestrial vertebrates (Pérez-Fernández et al. 2021). This common pattern of dopaminergic pathways, including the mesolimbic pathway to the nucleus accumbens, has been also identified in amphibians, although there are some anatomical differences compared to the mammalian brain (Marín et al. 1997; Yamamoto and Vernier 2011).

The ventral tegmental area has large portion of brain dopaminergic neurons with a high diversity of cell types, molecular properties, and electrophysiological properties in many mammalian species (Fu et al. 2012; Roeper 2013; Lammel et al. 2014; Walsh and Han 2014). Although, the ventral tegmental nucleus could be subdivided into 4–7 distinct subnuclei (Phillipson 1879; Cavalcanti et al. 2016), projections from the ventral tegmental area do not follow these subdivisions (Björklund and Lindvall 1984). The ventral tegmental neurons have two firing patterns with low-frequency tonic firing (1–5 Hz) and transient high-frequency burst or phasic firing (> 15 Hz) (Yim and Mogenson 1980; Grace and Onn 1989). These high-frequency firing episodes happen often, although in irregular intervals. Regularity of firing in the ventral tegmental area (A10) and the mean burst firing rate were reported in 23% for the A10 neurons. Similar slow and fast firing neurons were reported for the substantia nigra (Ruskin et al 1999), but such regularity of firing rate in substantia nigra was only in 3% of A9 neurons (Grenhoff et al. 1988).

The ascending dopaminergic axons can branch and lead to axonal arbors or axonal bushes (Matsuda et al. 2009) and have numerous varicosities along myelinated axons. In the substantia nigra, a single neuron can project to 1.5% of the total volume of the neostriatum via axonic arborization (Matsuda et al. 2009). Since it is difficult to study functions or varicosities in the whole brain, neuronal cultures were used. Some of the dopaminergic boutons were found silent and not releasing the transmitter, as studied in a cell culture (Pereira et al 2016). Using a near-infrared fluorescent dopamine nanosensor with a high spatial and temporal resolution in cultured murine dopaminergic neurons, it was found that dopamine release varied among the varicosities and some of them were silent, but about 17% of the varicosities showed hotspots of dopamine release (Elizarova et al. 2022). This mode of long-distance communication is consistent with volume transmission (Fuxe et al. 2010; Agnati and Fuxe 2014).

Cortical convergence of the emotional arousal systems

The ascending mesolimbic cholinergic as well as dopaminergic pathways of the emotional arousal system are diffuse, i.e., they have branching axons, create extensive terminal radiation and pose difficulties in precise localization of the terminal fields. Both systems have numerous, active varicosities along their axons. Their terminal synaptic contacts at the end of the axonal arbors are sometimes difficult or not possible to detect. These mesolimbic systems probably work by volume transmission (by transmitter diffusion through the cerebrospinal fluid or by transport by extracellular vesicles, Agnati and Fuxe 2014), which may explain prolonged latencies in inducing behavioral responses in pharmacological experiments and generally, the long duration of emotional responses.

Although the ascending mesolimbic cholinergic and dopaminergic components of the emotional arousal system are extensively targeting subcortical limbic regions, they have narrow and converging inputs to the medial prefrontal cortex (Björklund and Lindvall 1978; Satoh and Fibiger 1986; Fibiger and Vincent 1987; Alcaro et al. 2007). These inputs supply acetylcholine or dopamine, they can induce coordinated neuronal activity recorded as cortical rhythms, and they can regulate neural activity and behavior.

Four Hz oscillations in the medial prefrontal cortex are dopamine dependent (Parker et al. 2014). In a recent study, activation of D1-type dopamine receptors in the medial prefrontal cortex in mice was able to induce delta-frequency activity (1–4 Hz) by coordinated activity of neurons in this region (Kim and Narayanan 2019). Also, repeated tactile stimulation in rats induced a positive emotional state as measured by emission of 50 kHz calls, which is mediated by the mesolimbic dopaminergic system. Furthermore, it was recently shown that such tactile stimulation induced 50 kHz vocalizations accompanied by EEG theta oscillations (Shimoju 2023).

Conversely, application of carbachol into the medial prefrontal cortex induced high-frequency gamma oscillations (30–90 Hz) (Lemercier et al. 2017). Similar oscillations were induced by carbachol in the medial prefrontal cortex in sevoflurane anesthetized rats, and additionally were able to restore some level of animal consciousness (Pal et al. 2018). Carbachol induced gamma rhythms have been also observed in the rat hippocampal slices (Fellous and Sejnowski 2000), suggesting that these kinds of oscillations may be found throughout the brain in response to carbachol.

Synaptic changes in the medial prefrontal cortex initiated by cortical rhythms imposed by emotional arousal

Using microdialysis techniques in rats, it was shown that stress increases the release of both acetylcholine and dopamine whereas their release was minimized by preexposure to environmental enrichment (Del Arco et al. 2007; Segovia et al. 2009). Cholinergic and dopaminergic input into the prefrontal cortex result in network oscillations that interact with cortical rhythms originating from other circuits, for instance, the medial prefrontal cortex-hippocampus circuit via thalamic nucleus reuniens (Kuang et al. 2023), the dorsomedial prefrontal cortex-olfactory bulb circuit, or the medial prefrontal cortex-amygdalar circuit (Bagur et al. 2021). All these circuits may generate different ongoing network oscillations and create difficulty in pinpointing specific rhythms associated with emotional arousal. However, general observations of EEG rhythms during positive or negative affective states may provide important information about these rhythms and the underlying synaptic and molecular mechanisms that occur in the medial prefrontal cortex.

Social interactions are the best elicitors of emotional states. Social interactions during the active wake cycle induce positive affect. Conversely, social interactions during the sleep cycle induce negative affect with sleep deprivation being a robust trigger (Palmer and Alfano 2017; Burgdorf et al. 2019; Cajochen et al. 2002). Thus, when energized wake (positive affect) transitions to tiredness (negative affect) the social interaction cycle is completed comprising a regulatory mechanism for emotional arousal and its expression (Burgdorf et al. 2019; 2020).

EEG alpha rhythms predominate during wake and are associated with active behaviors and positive affect. Slow delta rhythms occur during the night and are the hallmark of non-REM sleep, but during wake are associated with negative affect (Clark et al. 1998; Cajochen et al. 2002; Kahneman et al. 2004; Burgdorf et al. 2020; Burgdorf and Moskal 2023). The fast and slow oscillations are associated with changes in synaptic activity. Weak synaptic activity has been shown to generate delta waves, whereas strong input elicits alpha waves (Fellous and Sejnowski 2000). Alpha frequencies enhance synaptic strength as shown by an increase in long-term potentiation (LTP), whereas delta frequencies decrease synaptic strength as shown by the enhancement of long-term depotentiation (LTD) (Malenka and Bear 2004).

The cholinergic and dopaminergic inputs to the medial prefrontal cortex, in addition to interacting with each other, modulate glutamate transmission and expression of glutamate receptors (Porras et al. 1997; Xue et al. 2018). Hedonic calls are associated with an upregulation of NMDA receptors, AMPA receptors, and growth factor receptors which lead to enhanced synaptic plasticity. Down-regulation of these receptors occurs during negative affect. In addition, the circadian rhythms of the expression of these synaptic proteins are thought to control wake and sleep (Tononi and Cirelli 2014; Wang et al. 2018). The relevant regulation of these receptors occurs in a circuit comprising the medial prefrontal cortex (the flexible/adaptable node of the circuit) which projects to the periaqueductal gray, which controls behavioral output (Burgdorf et al. 2020; Jürgens 1998; 2009). Therefore, aversive (cholinergic) and hedonic (dopaminergic) inputs to the medial prefrontal cortex may regulate switching from positive to negative affective states or vice versa mediated in part by the glutamatergic modulation of synaptic plasticity (Burgdorf and Moskal 2023). More studies are needed to fully understand these mechanisms.

Summary

This review presents the anatomy and the general functions of the ascending reticular systems for arousal. In addition to the widely developed reticular activating system for cognitive arousal, there are two ascending systems from the rostral part of reticular system that initiate emotional arousal. Negative emotional arousal is initiated by the ascending mesolimbic cholinergic pathway and positive emotional arousal is initiated by the ascending mesolimbic dopaminergic pathway. Both mesolimbic systems are diffuse in nature and release transmitters through numerous varicosities, mostly in subcortical forebrain limbic structures. Additionally, the cholinergic and dopaminergic emotional arousal systems have cojoined inputs into the medial prefrontal cortex and contribute to inducing relevant cortical EEG rhythms. It has been suggested that both cholinergic and dopaminergic inputs to the medial prefrontal cortex may also influence glutamate receptor activity. Positive emotional states are associated with fast EEG rhythms that enhance synaptic strength, while negative emotional states are associated with slow EEG rhythms that decrease synaptic strength. Switching from positive to negative emotional states and vice versa, is likely controlled by the ability of the medial prefrontal cortex. We suggest that there is a switch controlled by the medial prefrontal cortex that regulates positive and negative affective states.

Authors’ contributions

SMB, JSB and JRM contributed to the study conception and to writing the text. SMB and JSB wrote the initial draft of the paper, while JRM contributed to the final text. All authors read, reviewed, and approved the final manuscript.

Funding

The manuscript was not supported by any external funds.

Data availability

Enquiries about data availability should be directed to the authors of individual publications.

Declarations

Conflict of interest

The authors declare no competing interests. 

Footnotes

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