Biology subjects

Friedman, J. M.

Publications and source records attributed to Friedman, J. M..

3 recordsLinked to original sources

bioRxiv2018

Encoding of an engram for food location by satiety-promoting Drd2 hippocampal neurons

Associative learning guides feeding behavior in mammals in part by using cues that link location in space to food availability. However, the elements of the top-down circuitry encoding the memory of the location of food is largely unknown, as are the high-order processes that control satiety. Here we report that hippocampal dopamine 2 receptor (D2R) neurons are specifically activated by food and that modulation of their activity reduce food intake in mice. We also found that activation of these neurons interferes with the valence of food and the acquisition of a spatial memory linking food to a location via projections from the hippocampus to the lateral septum. Finally, we showed that inputs from lateral entorhinal cortex (LEC) to the hippocampus can also drive satiety via activation of D2R cells. These data describe a previously unidentified function for hippocampal D2R cells to regulate feeding behavior and identifies a LEC->Hippocampus->Septal high-order circuit that encodes the memory of food location.

animal behavior and cognition↗

bioRxiv2018

A non-canonical-PPARγ/RXRα-binding sequence regulates leptin expression in response to changes in adipose tissue mass

Leptin expression decreases after fat loss and is increased when obesity develops and its proper quantitative regulation is essential for the homeostatic control of fat mass. We previously reported that a distant leptin enhancer (LE1), 16kb upstream from the transcription start site (TSS), confers fat-specific expression in a BAC transgenic reporter mouse (BACTG). However this and the other elements that we identified do not account for the quantitative changes in leptin expression that accompany alterations of adipose mass. In this report, we used ATAC-seq to identify a 17bp non-canonical-PPAR{gamma}/RXR-binding site leptin regulatory element 1 (LepRE1) within LE1, and show that it is necessary for the fat-regulated quantitative control of reporter (luciferase) expression. While BACTG reporter mice with mutations in this sequence still show fat-specific expression, luciferase is no longer decreased after food restriction and weight loss. Similarly the increased expression of leptin reporter associated with obesity in ob/ob mice is impaired. A functionally analogous LepRE1 site is also found in a second, redundant DNA regulatory element 13kb downstream of the TSS. These data uncouple the mechanisms conferring qualitative and quantitative expression of the leptin gene and further suggest that factor(s) that bind to LepRE1 quantitatively control leptin expression and might be components of a lipid sensing system in adipocytes.\n\nSignificanceLeptin gene expression is highly correlated with the lipid content of individual fat cells suggesting that it is regulated by a \"fat sensing\" signal transduction pathway. This study is thus analogous to studies that led to the identification of a cholesterol-sensing pathway by studying the regulation of the LDL receptor gene by intracellular cholesterol. Several lines of investigation have suggested that, in addition to adipocytes, liver, neurons and other cell types can also sense changes in lipid content though the molecular mechanisms are unknown. The data here provide a critical first step toward elucidating the components of this system, which would be of great importance. These studies also identify a previously underappreciated role of PPAR{gamma}/RXR complex to regulate leptin expression.

physiology↗

bioRxiv2018

Control of non-homeostatic feeding in sated mice using associative learning of contextual food cues

Feeding is a complex motivated behavior controlled by a distributed neural network that processes sensory information to generate adaptive behavioral responses. Accordingly, studies using appetitive Pavlovian conditioning confirm that environmental cues that are associated with food availability can induce feeding even in satiated subjects. However, in mice, appetitive conditioning generally requires intensive training and thus can impede molecular studies that often require large numbers of animals. To address this, we developed and validated a simple and rapid context-induced feeding (ctx-IF) task in which cues associated with food availability can later lead to increased food consumption in sated mice. We show that the associated increase in food consumption is driven by both positive and negative reinforcement and that spaced training is more effective than massed training. Ctx-IF can be completed in [~]1 week and provides an opportunity to study the molecular mechanisms and circuitry underlying non-homeostatic eating. We have used this paradigm to map brain regions that are activated during Ctx-IF with cFos immunohistochemistry and found that the insular cortex, and other regions, are activated following exposure to cues denoting the availability of food. Finally, we show that inhibition of the insular cortex using GABA agonists impairs performance of the task. Our findings provide a novel assay in mice for defining the functional neuroanatomy of appetitive conditioning and identify specific brain regions that are activated during the development of learned behaviors that impact food consumption.

neuroscience↗