Food Restriction Engages Prefrontal Corticostriatal Cells and Local Microcircuitry to Drive the Decision to Run versus Conserve Energy

Abstract

Food restriction (FR) evokes running, which may promote adaptive foraging in times of food scarcity, but can become lethal if energy expenditure exceeds caloric availability. Here, we demonstrate that chemogenetic activation of either the general medial prefrontal cortex (mPFC) pyramidal cell population, or the subpopulation projecting to dorsal striatum (DS) drives running specifically during hours preceding limited food availability, and not during ad libitum food availability. Conversely, suppression of mPFC pyramidal cells generally, or targeting mPFC-to-DS cells, reduced wheel running specifically during FR and not during ad libitum food access. Post mortem c-Fos analysis and electron microscopy of mPFC layer 5 revealed distinguishing characteristics of mPFC-to-DS cells, when compared to neighboring non–DS-projecting pyramidal cells: 1) greater recruitment of GABAergic activity and 2) less axo-somatic GABAergic innervation. Together, these attributes position the mPFC-to-DS subset of pyramidal cells to dominate mPFC excitatory outflow, particularly during FR, revealing a specific and causal role for mPFC-to-DS control of the decision to run during food scarcity. Individual differences in GABAergic activity correlate with running response to further support this interpretation. FR enhancement of PFC-to-DS activity may influence neural circuits both in studies using FR to motivate animal behavior and in human conditions hallmarked by FR.

Feedback inhibition by GABAergic interneurons that are driven by dorsal raphe-projecting pyramidal neurons of the medial prefrontal cortex suppress feeding of adolescent female mice undergoing activity-based anorexia

“…Although both the PT (pyramidal tract) and IT (intratelencephalic) subpopulations of Layer 5 neurons in motor and somatosensory cortex project to DS and are thus considered CSt (Reiner, Jiao, Del Mar, Laverghetta, & Lei, 2003;Shepherd, 2013), the extent of mPFC's PT collaterals to DS (which would include the mPFCDR pyramidal cells studied here) is much less than for the mPFC's IT subpopulation of CSt pyramidal cells (Anastasiades & Carter, 2021). Both our previous (Santiago et al, 2021) and current ultrastructural analyses indicate that the mPFCDR/PT cells of Layer 5 belong to the subpopulation of neurons in Layer 5 of mPFC with greater GABAergic innervation. This agrees with electrophysiological studies indicating that the PT subpopulation of CSt in Layer 5 of mPFC are more strongly inhibited than are the IT-CSt neurons in Layer 5 (Anastasiades & Carter, 2021;Lee et al, 2014).…”

“…This means that microcircuits from DR-projecting Layer 5 pyramidal neurons feed back to Layers 2/3 of mPFC, in addition to the canonical cortical circuit with projections from Layers 2/3 pyramidal neurons to Layer 5 pyramidal neurons (Dhruv, 2015).While this type of feedback pathway from deeper to superficial layers as well as their functional implications are wellstudied in the visual cortex (reviewed in (Capone et al, 2016)), such circuits are less studied in the mPFC. At least some of the activated neurons in Layers 2/3 were pyramidal neurons which, in turn, are known to project to dorsal and ventral striatum (Jankowski & Sesack, 2004) and enhance wheel running during FR within the context of ABA (Santiago et al, 2021). Those activities may exert complicated effects that were intermingled with the roles of the DR-projecting neurons in regulating feeding of our ABA animals.…”

“…In this study, multiplex Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) were used to target the group of neurons projecting from mPFC to DR. The chemogenetic approach resembled the methods described in another recent publication from this lab, except that the Multiplexed-Retro DREADD induction targeted the mPFC-to-DR, rather than the mPFC pyramidal neurons projecting to dorsal striatum (Santiago et al, 2021).…”

“…In sum, ABA captures the following essential elements of AN: Severe weight loss, extensive exercise even during the limited hours of food availability, and anxiety. The significance of this model lies in its potential to shed light on the neurobiological underpinnings of anorexia-like behaviors in rodents (Chowdhury et al, 2019;Chowdhury, Wable, Sabaliauskas, & Aoki, 2013;Foldi, Milton, & Oldfield, 2017;Santiago, Makowicz, Du, & Aoki, 2021), through which the mechanism of as well as the treatments for patients with AN can be enlightened.…”

“…Anatomically, GABAergic interneurons (GABA-IN) in DR receive inputs from Layer 5 pyramidal neurons in the medial prefrontal cortex (mPFC) (Jankowski & Sesack, 2004). mPFC is implicated in various higher-order cognitive functions such as learning, memory and decision-making and have we have previously implicated this brain region in ABA running (Santiago et al, 2021). Activation of mPFC projections to DR (mPFCDR) induces active coping within adverse environments and challenges such as the forced swim test (Warden et al, 2012).…”