Periodic Reporting for period 3 - MotivatedBehaviors (Top down regulation of motivated behaviors by lateral septal integration of cortico-hippocampal inputs)
Période du rapport: 2024-01-01 au 2025-06-30
How does cognition regulate innate “low-level” behaviors? While the cognitive functions of the prefrontal cortex (PFC) and hippocampus have been extensively studied, we know much less about their ability to regulate the activity of the various hypothalamic nuclei controlling motivated behaviors (sociability, aggression, mating, feeding). Living in society nonetheless requires that our past experiences and decision-making exert some degree of control over our “basic” behaviors. The lateral septum (LS) -receiving inputs from PFC and hippocampus and projecting primarily to the hypothalamus- is ideally positioned to integrate cognitive information and, in turn, regulate motivated behaviors. Thus I characterized in mice a novel circuit by which hippocampal CA2 projections to LS result in disinhibition of an aggression-promoting nucleus of the hypothalamus. I also showed that vasopressin enhances aggression through presynaptic facilitation of CA2 inputs to LS. Using this study as a blueprint, I will determine the logic by which LS integrates and compute cognitive inputs to regulate other motivated behaviors. As motivated behaviors depend on internal states, I will also explore how modulatory inputs (vasopressin, dopamine, serotonin) from subcortical brain regions to LS can regulate its function. Finally, since hippocampus, PFC and LS are implicated in several psychiatric disorders associated with altered social behaviors (schizophrenia, autism or bipolar disorder), insights into how these regions regulate motivated behaviors are critical for understanding both basic neural mechanisms as well as how disease processes lead to altered social interactions. This project therefore also aims to unravel potential changes occurring in disorders associated with social behavioral deficits with the ultimate goal of providing new therapeutic targets for disease treatment. Thus my study may suggest new approaches to treat abnormal social cognition associated with psychiatric disorders.
We first investigated a neuromodulatory projection from the pre-frontal cortex (PFC) to the lateral septum. Corticotropin-releasing hormone (CRH)-expressing neurons from the infra-limbic area of the PFC are activated by social familiarity cues from the ventral hippocampus and release CRH in the lateral septum to disinhibit it and suppress social interaction with familiar mice. This participates in the social novelty preference exhibited in many adult rodents. Unlike adult rodents, young rodents display preference for their own siblings and mother over novel individuals. The work of Hepper (1983) and others have shown that this preference shifts during the post-natal period to allow adult rodents to display social novelty preference. Our study further demonstrates how the maturation of CRH expression during the first two post-natal weeks enables a developmental shift from a preference for littermates in juveniles to a preference for novel mice in adults.
In another project, we characterized a novel projection from the bed nucleus of the stria terminalis to the lateral septum and demonstrated its role in sociability and social aggression. We further demonstrated that this projection was impaired in a mouse model of psychiatric disease associated with impaired social behaviors.
In a third project, we leveraged snRNAseq of the septum to identify dysregulated neuronal clusters in a mouse model of schizophrenia. We identified several dysregulated clusters as well as neuronal markers to target them. We then leveraged Cre-specific mouse lines to investigate the function of these LS neurons in WT mice.
In another project, we characterized a novel projection from the bed nucleus of the stria terminalis to the lateral septum and demonstrated its role in sociability and social aggression. We further demonstrated that this projection was impaired in a mouse model of psychiatric disease associated with impaired social behaviors.
In a third project, we leveraged snRNAseq of the septum to identify dysregulated neuronal clusters in a mouse model of schizophrenia. We identified several dysregulated clusters as well as neuronal markers to target them. We then leveraged Cre-specific mouse lines to investigate the function of these LS neurons in WT mice.
To the best of our knowledge, our study of CRH release in LS is the first one linking the recall of a social memory (social familiarity detection) to the behavioral read-out (decreased interaction time). We believe our results to be of particular significance as social preference, the decision to interact with one member of the same species over another, is a key feature of optimizing social interactions. In addition, impaired social interactions are often associated with the onset of many psychiatric disorders and the regions implicated in our study are known to be dysregulated during psychiatric disorders. We therefore believe our findings to have potential translational applications for the development of new treatments of social anxiety disorders, including separation or avoidant personality disorders which are associated with an aversion for social interactions with novel individuals. Furthermore, CRH has been involved in various anxiety disorders, including social phobia. This led us to propose that lower CRH levels in the PFC might prevent patients from seeking novelty. We are now investigating several identified LS populations to understand how they integrate cortical inputs and branch out to the hypothalamus in order to orchestrate motivated behaviors. We also intend to submit a proof-of-concept grant aiming at testing, in rodent models, new treatments for social anxiety disorders such as separation anxiety or avoidant personality disorders,
We are also finalizing 2 separate studies of mouse models of psychiatric diseases, trying to rescue impaired social behaviors. To do this, we are leveraging the results obtained previously in WT mice regarding neuronal and neuromodulatory septal circuits regulating social behaviors. We expect these results to have significant translational implications to treat the abnormal social behaviors exhibited by many patients affected with mental disorders.
We are also finalizing 2 separate studies of mouse models of psychiatric diseases, trying to rescue impaired social behaviors. To do this, we are leveraging the results obtained previously in WT mice regarding neuronal and neuromodulatory septal circuits regulating social behaviors. We expect these results to have significant translational implications to treat the abnormal social behaviors exhibited by many patients affected with mental disorders.