Biology subjects

Subramanian, K. S.

Publications and source records attributed to Subramanian, K. S..

6 recordsLinked to original sources

bioRxiv2025

The vagus nerve promotes memory via septo-hippocampal acetylcholine: Implications for obesity-induced cognitive dysfunction

The vagus nerve relays critical metabolic information between the gastrointestinal (GI) tract and the brain. Recent findings highlight a role for vagus nerve-mediated gut-brain signaling in regulating higher-order cognitive processes, although the underlying mechanisms remain poorly understood. Here we demonstrate that nutrient consumption promotes hippocampal-dependent memory function via vagus nerve-mediated acetylcholine (ACh) release in the dorsal hippocampus (HPCd) from medial septum (MS) neurons. In vivo analyses reveal that HPCd ACh release is engaged during nutrient consumption, and that this response is abolished in animals that received MS cholinergic neuron ablation, subdiaphragmatic vagotomy (SDV), or early-life Western Diet (WD) maintenance. MS cholinergic neuron ablation, SDV, and early-life WD also impaired memory for meal location, suggesting that this gut-brain pathway functions to encode memories for eating events. Collectively, results identify a neurobiological mechanism whereby nutrient consumption promotes memory function, and reveal that disruption of this vagal-brain signaling system mediates WD-associated memory impairments.

neuroscience↗

bioRxiv2023

Early- but not late-adolescent Western diet consumption programs for long-lasting memory impairments in male but not female rats

Early life Western diet (WD) consumption leads to impaired memory function, particularly for processes mediated by the hippocampus. However, the precise critical developmental window(s) during which WD exposure negatively impacts hippocampal function are unknown. Here, we exposed male and female rats to a WD model involving free access to a variety of high-fat and/or high-sugar food and drink items during either the early-adolescent period (postnatal days [PN] 26-41; WD-EA) or late-adolescent period (PN 41-56; WD-LA). Control (CTL) rats were given healthy standard chow throughout both periods. To evaluate long-lasting memory capacity well beyond the early life WD exposure periods, we performed behavioral assessments after both a short (4 weeks for WD-EA, 2 weeks for WD-LA) and long (12 weeks for WD-EA, 10 weeks for WD-LA) period of healthy diet intervention. Results revealed no differences in body weight or body composition between diet groups, regardless of sex. Following the shorter period of healthy diet intervention, both male and female WD-EA and WD-LA rats showed deficits in hippocampal-dependent memory compared to CTL rats. Following the longer healthy diet intervention period, memory impairments persisted in male WD-EA but not WD-LA rats. In contrast, in female rats the longer healthy diet intervention reversed the initial memory impairments in both WD-EA and WD-LA rats. Collectively, these findings reveal that early-adolescence is a critical period of long-lasting hippocampal vulnerability to dietary insults in male but not female rats, thus highlighting developmental- and sex-specific effects mediating the relationship between the early life nutritional environment and long-term cognitive health.

animal behavior and cognition↗

bioRxiv2023

Ventral hippocampus neurons encode meal-related memory

The ability to encode and retrieve meal-related information is critical to efficiently guide energy acquisition and consumption, yet the underlying neural processes remain elusive. Here we reveal that ventral hippocampus (HPCv) neuronal activity dynamically elevates during meal consumption and this response is highly predictive of subsequent performance in a foraging-related spatial memory task. Targeted recombination-mediated ablation of HPCv meal-responsive neurons impairs foraging-related spatial memory without influencing food motivation, anxiety-like behavior, or escape-mediated spatial memory. These HPCv meal-responsive neurons project to the lateral hypothalamic area (LHA) and single-nucleus RNA sequencing and in situ hybridization analyses indicate they are enriched in serotonin 2a receptors (5HT2aR). Either chemogenetic silencing of HPCv-to-LHA projections or intra-HPCv 5HT2aR antagonist yielded foraging-related spatial memory deficits, as well as alterations in caloric intake and the temporal sequence of spontaneous meal consumption. Collective results identify a population of HPCv neurons that dynamically respond to eating to encode meal-related memories.

neuroscience↗

bioRxiv2023

Western diet consumption impairs memory function via dysregulated hippocampus acetylcholine signaling

Western diet (WD) consumption during development yields long-lasting memory impairments, yet the underlying neurobiological mechanisms remain elusive. Here we developed an early life WD rodent model to evaluate whether dysregulated hippocampus (HPC) acetylcholine (ACh) signaling, a pathology associated with memory impairment in human dementia, is causally-related to WD-induced cognitive impairment. Rats received a cafeteria-style WD (access to various high-fat/high-sugar foods; CAF) or healthy chow (CTL) during the juvenile and adolescent periods (postnatal days 26-56). Behavioral, metabolic, and microbiome assessments were performed both before and after a 30-day healthy diet intervention beginning at early adulthood. Results revealed CAF-induced HPC-dependent contextual episodic memory impairments that persisted despite healthy diet intervention, whereas CAF was not associated with long-term changes in body weight, body composition, glucose tolerance, anxiety-like behavior, or gut microbiome. HPC immunoblot analyses after the healthy diet intervention identified reduced levels of vesicular ACh transporter in CAF vs. CTL rats, indicative of chronically reduced HPC ACh tone. To determine whether these changes were functionally related to memory impairments, we evaluated temporal HPC ACh binding via ACh-sensing fluorescent reporter in vivo fiber photometry during memory testing, as well as whether the memory impairments could be rescued pharmacologically. Results revealed dynamic HPC ACh binding during object-contextual novelty recognition was highly predictive of memory performance and was disrupted in CAF vs. CTL rats. Further, HPC alpha-7 nicotinic receptor agonist infusion during consolidation rescued memory deficits in CAF rats. Overall, these findings identify dysregulated HPC ACh signaling as a mechanism underlying early life WD-associated memory impairments.

neuroscience↗

bioRxiv2022

Hypothalamic melanin-concentrating hormone neurons integrate food-motivated appetitive and consummatory processes

The lateral hypothalamic area (LHA) integrates homeostatic processes and reward-motivated behaviors. Here we show that LHA neurons that produce melanin-concentrating hormone (MCH) are dynamically responsive to both food-directed appetitive and consummatory processes. Specifically, our results reveal that MCH neuron Ca+2 activity increases in response to both discrete and contextual food-predictive cues and is correlated with food-motivated responses. MCH neuron activity also increases during eating and this response is highly predictive of caloric consumption and declines throughout a meal, thus supporting a role for MCH neurons in the positive feedback consummatory process known as appetition. These physiological MCH neural responses are functionally-relevant as chemogenetic MCH neuron activation promotes appetitive behavioral responses to food-predictive cues and increases meal size. Finally, MCH neuron activation enhances preference for a noncaloric flavor paired with intragastric glucose. Collectively, these data identify a hypothalamic neural population that orchestrates both food-motivated appetitive and intake-promoting consummatory processes.

neuroscience↗

bioRxiv2020

Central oxytocin signaling inhibits food reward-motivated behaviors and VTA dopamine responses to food-predictive cues

Oxytocin potently reduces food intake and is a potential target system for obesity treatment. A better understanding of the behavioral and neurobiological mechanisms mediating oxytocins anorexigenic effects may guide more effective obesity pharmacotherapy development. The present study examined the effects of central (lateral intracerebroventricular [ICV]) administration of oxytocin in rats on motivated responding for palatable food. Various conditioning procedures were employed to measure distinct appetitive behavioral domains, including food seeking in the absence of consumption (conditioned place preference expression), impulsive responding for food (differential reinforcement of low rates of responding), effort-based appetitive decision making (high-effort palatable vs. low-effort bland food), and postingestive reward value encoding (incentive learning). Results reveal that ICV oxytocin potently reduces food-seeking behavior, impulsivity, and effort-based palatable food choice, yet does not influence encoding of postingestive reward value in the incentive learning task. To investigate a potential neurobiological mechanism mediating these behavioral outcomes, we utilized in vivo fiber photometry in ventral tegmental area (VTA) dopamine neurons to examine oxytocins effect on phasic dopamine neuron responses to sucrose-predictive Pavlovian cues. Results reveal that ICV oxytocin significantly reduced food cue-evoked dopamine neuron activity. Collectively, these data reveal that central oxytocin signaling inhibits various obesity-relevant conditioned appetitive behaviors, potentially via reductions in food cue-driven phasic dopamine neural responses in the VTA. HighlightsO_LICentral oxytocin inhibits motivated responding for palatable food reinforcement C_LIO_LICentral oxytocin does not play a role in encoding postingestive reward value C_LIO_LICentral oxytocin blunts VTA dopamine neuron activity in response to food cues C_LI

neuroscience↗