Thursday, April 3, 2025
4/3/2025
Identifying a role for the lateral habenula in typical and perturbed social behavior development - Project Summary For many species, access to resources requires a highly flexible system of social behavior that is sensitive to environmental demands. Indeed, inflexible social behavior can be highly maladaptive, particularly during developmental transitions when social demands are in constant flux. Yet, the neural substrates supporting flexible social behavior during development have been underexplored. Due to technical limitations, it has been challenging to identify the circuits responsible for social cue processing in the infant brain and how these go awry in atypical development. Using recent advances in infant rodent neural circuit dissection, this proposal aims to address this gap in our understanding. We focus on the lateral habenula (LHb) and its connections with the medial prefrontal cortex (mPFC) because this circuit is critical for behavioral flexibility in adults. We propose a central hypothesis that functional inclusion of the LHb in the social behavior circuit transitions a system favoring social approach within the nest to one favoring a balance of approach and avoidance as infants gain independence and enter the complex social world. This transition is postulated to occur via enhanced modulation by the mPFC at weaning age. The goal of this proposal is to test this hypothesis using advanced circuit dissection tools in the pre-weaning (PN14) and post-weaning (PN23) rat pup across three Aims. First, we will ask how LHb engagement controls transitions in social behavior during typical development. To address this question, we will use complementary ex vivo (metabolic imaging, Aim 1a) and in vivo approaches (fiber photometry, Aim 1b) to measure LHb function during social behavior in PN14 and PN23 animals. Then we will assess causation by optogenetically controlling LHb activity during social behavior at these two ages (Aim 1c). As the LHb is distinctive for its role as a relay center between the forebrain and monoaminergic centers in guiding behavior, Aim 2 is designed to assess how LHb circuits control developmental transitions in social behavior. In this Aim, we will assess network-level changes of 2-DG uptake during social behavior in extended LHb circuits as a function of development (PN14 versus PN23) (Aim 2a). Next, we will measure (photometry) and manipulate (optogenetics) identified projections at both ages to determine their role in developmental transitions in social approach (Aims 2b-c). Finally, we will use a multiplexed chemogenetic approach to simultaneously control LHb network populations to determine their respective roles in behavioral transitions (Aim 2d). The goal of Aim 3 is to leverage the advanced circuit mapping techniques described in Aims 1 & 2 to test the hypothesis that caregiving adversity accelerates LHb inclusion in social behavior networks to prematurely inhibit social approach. By perturbing this system while it is still being built, the proposed experiments will identify how early experience sculpts developing LHb circuit architecture to generate maladaptive social behavior. Together, these studies will provide a technical and conceptual advance in our understanding of the developing social brain and the impact of perturbing this delicate system.
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