Pharmacological Inactivation of Medial Prefrontal Cortex Does Not Support Dichotomous “Go/Stop” Roles for Dorsal and Ventral Subdivisions in Natural Reward Seeking in Rats

AbstractThe paraventricular nucleus (PVT) of the midline thalamus is a critical higher-order cortico-thalamo-cortical integration site that plays a critical role in various behaviors including reward seeking, cue saliency, and emotional memory. Anatomical studies have shown that PVT projects to both medial prefrontal cortex (mPFC) and hippocampus (HC). However, dual mPFC-HC projecting neurons which could serve a role in synchronizing mPFC and HC activity during PVT-dependent behaviors, have not been explored. Here we used a dual retrograde adenoassociated virus (AAV) tracing approach to characterize the location and proportion of different projection populations that send collaterals to mPFC and/or ventral hippocampus (vHC). Additionally, we examined the distribution of calcium binding proteins calretinin (CR) and calbindin (CB) with respect to these projection populations PVT. We found that PVT contains separate populations of cells that project to mPFC, vHC, and those that innervate both regions. Interestingly, dual mPFC-HC projecting cells expressed neither CR or CB. Topographically, mPFC- and vHC-projecting CB+ and CR+ cells clustered around dual projecting neurons in PVT. These results are consistent with the features of dual mPFC-vHC projecting cells in the nucleus reuniens (RE) and suggestive of a functional mPFC-PVT-vHC system that may support mPFC-vHC interactions in PVT-dependent behaviors.

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Identification of a stress-sensitive anorexigenic neurocircuit from medial prefrontal cortex to lateral hypothalamus in humans and mice

10.1101/2021.09.07.459350 ◽

2021 ◽

Author(s):

Rachel E Clarke ◽

Katharina Voigt ◽

Romana Stark ◽

Urvi Bharania ◽

Harry Dempsey ◽

...

Keyword(s):

Prefrontal Cortex ◽

Food Intake ◽

Medial Prefrontal Cortex ◽

Lateral Hypothalamus ◽

Acute Stress ◽

Mild Stress ◽

Potential Threat ◽

Reward Seeking ◽

Neural Network Dynamics ◽

Predictive Assessment

AbstractAnimal models that examine neural circuits controlling food intake often lack translational relevance. To address this limitation, we identified neural network dynamics related to homeostatic state and BMI in humans. This approach predicted a novel pathway projecting from the medial prefrontal cortex (mPFC) to the lateral hypothalamus (LH) in humans. We then dissected the mechanistic underpinnings of this human-relevant mPFC-LH circuit in mice. Chemogenetic or optogenetic activation of the mPFC-LH pathway in mice suppressed food intake and motivated sucrose-seeking. Fibre photometry demonstrated this pathway was active in response to acute stress or prior to novel environment or object exposure, suggesting a role in the predictive assessment of potential threat. Food consumption suppressed mPFC-LH neuronal activity, independent of metabolic state or palatability. Finally, inhibition of this circuit increased feeding and motivated behaviour under mild stress and chronic ablation caused weight gain. These studies identify the mPFC-LH as a novel stress-sensitive anorexigenic neural pathway involved in the cortical control of food intake and motivated reward-seeking.

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