Adolescent females are particularly vulnerable to mental illnesses with comorbidity of anxiety, such as anorexia nervosa (AN). We used an animal model of AN, called activity-based anorexia (ABA), to investigate the neurobiological basis of vulnerability to repeated, food restriction (FR) stress-evoked anxiety. Twenty-one of 23 adolescent female mice responded to the 1st FR with increased wheel running activity (WRA), even during the limited period of food access, thereby capturing AN's symptoms of voluntary FR and over-exercise. Baseline WRA was an excellent predictor of FR-elicited WRA (severity of ABA, SOA), with high baseline-runners responding to FR with minimal SOA (i.e., negative correlation). Nine gained resistance to ABA following the 1st FR. Even though allopregnanolone (3α-OH-5α-pregnan-20-one, THP), the metabolite of progesterone (P4), is a well-recognized anxiolytic agent, subcutaneous P4 to these ABA-resistant animals during the 2nd FR was exacerbative, evoking greater WRA than the counterpart resistant group that received oil vehicle, only. Moreover, P4 had no WRA-reducing effect on animals that remained ABA-vulnerable. To explain the sensitizing effect of P4 upon the resistant mice, we examined the relationship between P4 treatment and levels of the α4 subunit of GABAARs at spines of pyramidal cells of the hippocampal CA1, a parameter previously shown to correlate with resistance to ABA. α4 levels at spine membrane correlated strongly and negatively with SOA during the 1st ABA (prior to P4 injection), confirming previous findings. α4 expression levels were greater among P4-treated animals that had gained resistance than of vehicle-treated resistant animals or of the vulnerable animals with or without P4. We propose that α4-GABAARs play a protective role by counterbalancing the ABA-induced increase in excitability of CA1 pyramidal neurons, and although exogenous P4's metabolite, THP, enhances α4 expression, especially among those that can gain resistance, it also interferes with α4-GABAARs’ protective role by desensitizing α4-GABAARs.

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Dendrites of pyramidal neurons integrate different sensory inputs, and non-linear dendritic computations drive feature selective tuning and plasticity. Yet little is known about how dendrites themselves represent the environment, the degree to which they are coupled to their soma, and how that coupling is sculpted with experience. In order to answer these questions, we developed a novel preparation in which we image soma and connected dendrites in a single plane across days using in vivo two-photon microscopy. Using this preparation, we monitored spatially tuned activity in area CA3 of the hippocampus in head-fixed mice running on a linear track. We identified “place dendrites”, which can stably and precisely represent both familiar and novel spatial environments. Dendrites could display place tuning independent of their connected soma and even their sister dendritic branches, the first evidence for branch-specific tuning in the hippocampus. In a familiar environment, spatially tuned somata were more decoupled from their dendrites as compared to non-tuned somata. This relationship was absent in a novel environment, suggesting an experience dependent selective gating of dendritic spatial inputs. We then built a data-driven multicompartment computational model that could capture the experimentally observed correlations. Our model predicts that place cells exhibiting branch-specific tuning have more flexible place fields, while neurons with homogenous or co-tuned dendritic branches have higher place field stability. These findings demonstrate that spatial representation is organized in a branch-specific manner within dendrites of hippocampal pyramidal cells. Further, spatial inputs from dendrites to soma are selectively and dynamically gated in an experience-dependent manner, endowing both flexibility and stability to the cognitive map of space.One sentence summaryHippocampal pyramidal cells show branch-specific tuning for different place fields, and their coupling to their soma changes with experience of an environment.

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Anatomically segregated apical and basal dendrites of pyramidal neurons receive functionally distinct inputs, but it is unknown if this results in compartment-level functional diversity during behavior. Here we imaged calcium signals from apical dendrites, soma, and basal dendrites of pyramidal neurons in area CA3 of mouse hippocampus during head-fixed navigation. To examine dendritic population activity, we developed computational tools to identify dendritic regions of interest and extract accurate fluorescence traces. We identified robust spatial tuning in apical and basal dendrites, similar to soma, though basal dendrites had reduced activity rates and place field widths. Across days, apical dendrites were more stable than soma or basal dendrites, resulting in better decoding of the animal’s position. These population-level dendritic differences may reflect functionally distinct input streams leading to different dendritic computations in CA3. These tools will facilitate future studies of signal transformations between cellular compartments and their relation to behavior.