Role of the Thalamic Reticular Nucleus in Social Memory

Social behaviors are crucial for gregarious animals, including humans. In order to exhibit appropriate behaviors in a complex social context, such as mating, aggression, avoidance, and cooperation, individuals need to remember their previous experiences with other members and accurately recognize them when they meet again. This ability is called “social memory” [1]. Many psychiatric disorders in humans, such as autism spectrum disorder, attention deficit hyperactivity disorder, and schizophrenia, are characterized by social memory impairments. Patients with these disorders, along with corresponding animal models, often show defects associated with the thalamic reticular nucleus (TRN). The TRN, a thin layer of neurons surrounding the thalamus, mainly regulates and coordinates the transfer of information between the cortex and the thalamus, playing a role in higher brain functions such as consciousness, attention, and sensory processing. However, whether the TRN is involved in social memory remains unknown.

In an article published in Neuron, Wang and colleagues [2] provide evidence that the TRN plays a crucial role in modulating social memory. Given the natural inclination of mice to spend more time exploring novel mice than familiar ones, the authors used this trait to evaluate their social memory. First, the authors demonstrated that the parvalbumin-positive (PV⁺) neurons, which predominate in the TRN, are significantly activated when the subject mouse encounters a familiar mouse (FM) compared to a novel mouse (NM) or a familiar object, suggesting that TRN^Pvalb neurons play a role in regulating social memory. Consistent with this, chemogenetic inhibition of PV⁺ neurons in the sensory TRN (sTRN) but not the limbic TRN induces short-term (10 min) social memory impairment. Conversely, activating sTRN^Pvalb enhances short-term social memory and extends social memory to at least 2 h. In contrast, manipulation of the activity of sTRN^Pvalb neurons has no effect on sociability or object memory. Together, these results indicate that sTRN^Pvalb neurons play a specific role in the regulation of social memory.

To determine the neural circuit mechanism of sTRN^Pvalb neurons in regulating social memory, the authors explored their downstream target and found that the parafascicular thalamic nucleus (PF) receives strong input from them. Consistent with the results of manipulation of sTRN^Pvalb neurons, optogenetic activation and inhibition of the sTRN^Pvalb→PF pathway significantly enhance and impair social memory, respectively. These findings demonstrate that sTRN^Pvalb neurons regulate social memory through their innervation of the PF. Next, the authors applied retrograde tracing to investigate the upstream input to the sTRN that regulates social memory. They found a large number of neurons mainly expressing CaMKIIα in the posterior parietal cortex (PPC). Moreover, manipulation of the activity of the PPC^CaMKII→sTRN pathway bidirectionally modulated social memory. To further investigate whether the sTRN^Pvalb neurons receiving PPC^CaMKIIα inputs play a role in regulating social memory through the PF, the authors designed a series of elaborate experiments. They found that apoptosis of PPC neurons projecting to the sTRN reduced the GABA concentration in the PF. In addition, activation of the PPC^CaMKII→sTRN pathway reduced the activity of PF neurons during social investigation and enhanced social memory. These phenomena were eliminated following the injection of picrotoxin, a GABA receptor antagonist, into the PF. Together, these results demonstrate that the PPC^CaMKII→sTRN^Pvalb→PF circuit regulates social memory (Fig. 1).

Fig. 1.

Schematic of the action of the sTRN in regulating social memory. The sTRN contains a population of inhibitory cells that are reactivated upon encountering a familiar mouse, termed social memory engram cells. This population of cells forms the foundation for storing and retrieving social memory. Social engram cells in the sTRN receive excitatory inputs from the PPC, and the PPC→sTRN pathway plays a role in regulating social memory by releasing GABA into the PF. The figure was created with BioRender.com

Memories are considered to be stored by sparsely distributed neurons [3]. Then is there a specific population of neurons in the sTRN that stores social memory? The authors further explored the single-cell mechanisms by which the sTRN regulates social memory. Interestingly, sTRN neurons that were activated during the first social interaction were reactivated when interacting with the same mouse for a second time but not with a novel mouse, suggesting the presence of social memory engram cells in the sTRN (sTRN^SMECs). Artificially activating sTRN^SMECs was able to retrieve social memory that was not recalled by natural social cues. The authors also examined the functional alterations of sTRN^SMECs, which is one of the main features of engram cells [3]. Compared to sTRN^non-SMECs, sTRN^SMECs exhibited enhanced excitability, more complex dendritic structures, and increased transcription levels of genes associated with protein synthesis. These findings indicate that changes at the cellular and molecular levels in sTRN^SMECs are the basis for social memory storage and retrieval (Fig. 1).

Wang and colleagues demonstrated that engram cells responsible for storing social memory exist in the sTRN, helping us understand the flow of information within the social memory neural network. The formation of social memory initially requires sensory inputs from conspecifics, such as olfactory, somatosensory, auditory, and visual cues, representing specific features of different sensory modalities. Multimodal sensory information is then integrated to form a memory of the identity of a conspecific. Further, concrete social memory is encoded into abstract social memory [1], such as emotional memories of conspecifics and memories of established social rank, which guide social behavior decisions in mice, such as avoidance or approach, compliance or dominance. In addition to sTRN, engram cells responsible for social memory have also been identified in the ventral hippocampus CA1 (vCA1) [4] and medial prefrontal cortex (mPFC) [5]. These regions are thought to represent different nodes within the social memory neural network and play distinct roles. The sTRN processes sensory information through its projection to the thalamus, which further transmits sensory information to somatosensory, auditory, and visual cortices, modulating their respective functions. Considering the critical role of the sTRN in processing certain social sensory information, it is possible that it is involved in perceiving and remembering specific features of conspecifics. The hippocampus is considered to be a region that integrates sensory information, receiving extensive projections from the olfactory cortex as well as the somatosensory, auditory, and visual cortices. Different subregions of the hippocampus play distinct roles in social memory. Novel conspecifics lead to increased firing of dorsal hippocampus CA2 (dCA2) neurons, suggesting that dCA2 may play a role in the processing and integrating of information related to novel conspecifics, which is fundamental to forming social memory. In contrast, vCA1 neurons are activated when encountering familiar conspecifics, indicating that it is involved in the storage of social memory of previously encountered conspecifics [1]. This evidence suggests that the hippocampus may store social memory of conspecific identity by receiving and processing multimodal social sensory information. The memory and recognition of conspecifics ultimately shape appropriate social behaviors. This process necessitates the involvement of higher cortical areas, such as the mPFC, which is integral to social cognition and the execution of behavioral decisions. For mice to effectively navigate their social environment, they recall the identities of conspecifics, then avoid threatening individuals, approach friendly ones, comply with higher-ranking ones, and maintain dominance over lower-ranking ones. Manipulating the mPFC affects not only the recognition of familiar and unfamiliar mice [5] but also learned social avoidance behaviors [6] and compliance or dominance behaviors toward conspecifics. These findings suggest that mPFC neurons transform memories of conspecific features into abstract social emotions and social rank memories, thereby guiding social behavior decisions.

In recent years, some studies have suggested that engram cells can be divided into two states, active or silent engrams, based on whether they can be reactivated by natural retrieval cues. Memory recall depends on the active engrams, while the silent engrams are associated with amnesia [3]. This distinction helps us to better understand social memory and social memory deficits. The authors found that when the interval between encoding (S2) and recall (S3) was 10 min, social memory could be recalled by natural social cues, indicating the existence of active engrams in the sTRN. However, after 7 days, social memory could only be recalled by artificial activation of sTRN engram cells but not by natural social cues [2], suggesting a transformation from active to silent engrams. The transformation between active and silent engrams is one normal way by which the brain regulates mnemonic processes, often involving physiological and structural changes in the engrams [3]. However, abnormal transformations can lead to behavioral deficits. A previous study reported that, in a model of Alzheimer's disease (AD), mice exhibit a contextual fear memory deficit because active engrams in the DG are replaced by silent engrams with reduced spine density. Rescue of the reduced spinal density of silent engrams can transform them into active engrams and promote the recovery of natural memory recall [7]. In addition, deficits in social memory, including anterograde and retrograde amnesia, are major symptoms of AD [8]. However, the role of the sTRN in social memory deficits among AD patients remains unclear. One of the main causes of AD is the accumulation of amyloid-beta (Aβ) [9], which can impair the formation of neuronal spines or lead to their loss. This raises the possibility that Aβ accumulation influences the formation of new social memory engram cells by inhibiting the development of sTRN neuronal spines during the process of anterograde social memory forgetting in AD. In retrograde social memory forgetting, Aβ accumulation promotes the loss of spines in active sTRN engrams, transforming them into the silent state and resulting in the forgetting of previously formed social memories. Interestingly, chronic activation of the TRN has been shown to reduce Aβ accumulation [10]. Therefore, the reduction of Aβ following chronic activation of the TRN may facilitate the formation of new social memory engram cells, while simultaneously inhibiting the transition of already established social memory active engrams to silent engrams. This could help mitigate both anterograde and retrograde forgetting of social memory in AD. On the other hand, direct enhancement of the activity of sTRN social memory silent engrams through acute activation also demonstrates the potential for alleviating retrograde forgetting of social memory [2]. Collectively, these findings suggest that targeting the sTRN holds promise for the treatment of the social memory deficits associated with AD.

Conflict of interest

The authors declare that thy have no conflict of interest.