Biology subjects

Kutlu, M. G.

Publications and source records attributed to Kutlu, M. G..

7 recordsLinked to original sources

bioRxiv2026

Dorsomedial striatal GABA dynamics organize palatable reward consumption and are reshaped by GLP-1 receptor agonism

Palatability and metabolic state strongly shape food consumption, making it important to understand the neural mechanisms that integrate these influences. Glucagon-like peptide-1 (GLP-1) receptor agonists are potent modulators of food intake and increasingly used therapeutic options, yet the circuit mechanisms underlying their effects remain unclear. Dorsal striatal inhibitory circuits contribute to reward-guided behavior and feeding, but how they encode ongoing consumption or are altered by GLP-1 receptor agonism is unknown. Using fiber photometry in mice, we found that dorsomedial striatal (DMS) GABA signals decreased at consumption onset, scaled with palatability, predicted licking, and were enhanced by food deprivation. GLP-1 receptor agonist semaglutide reduced intake, disrupted coupling between DMS GABA and licking, enhanced rebound signals preceding pauses, and increased DMS ensemble synchrony. Optogenetic excitation of DMS GABAergic interneurons reproduced key semaglutide-induced changes in consumption structure. These findings suggest that DMS GABA dynamics, as a state-dependent regulator of palatable consumption, are reshaped by GLP-1 receptor agonism.

neuroscience↗

bioRxiv2025

Dorsolateral striatal acetylcholine reorganizes neural ensembles to anticipate threat

Adaptive behavior requires flexible encoding of emotional valence. Although striatal acetylcholine (ACh) signaling is critical for reinforcement learning, its contribution to aversive learning has remained poorly defined. Here, we demonstrate that ACh release in the dorsolateral striatum (DLS) is selectively biased toward negative valence. Using fiber photometry with a genetically encoded ACh sensor, we found that ACh release robustly increased during threat prediction but decreased in anticipation of rewarding outcomes, revealing a bidirectional and valence-specific signature. Optogenetically stimulating ACh release at cue onset accelerated threat learning, impaired extinction, and shifted behavioral responding toward persistent threat expectancy. Concurrent single-cell calcium imaging and optogenetic manipulation revealed that elevated ACh release dynamically reorganized DLS ensemble activity, increasing both excited and inhibited neurons and producing large-scale state-space divergence during threat cues. During extinction, optogenetically sustained ACh release preserved the organization of threat-predictive DLS ensemble activity despite the absence of shock. These findings identify DLS ACh as a valence-specific neuromodulatory signal that reconfigures striatal network dynamics, primes ensembles for impending threat, and biases learning toward threat persistence.

neuroscience↗

bioRxiv2023

Nucleus accumbens core single cell ensembles bidirectionally respond to experienced versus observed aversive events

Empathy is the ability to adopt others sensory and emotional states and is an evolutionarily conserved trait among mammals. In rodents, empathy manifests itself as social modulation of aversive stimuli such as acknowledging and acting on conspecifics distress. The neuronal network underlying social transmission of information is known to overlap with the brain regions that mediate behavioral responses to aversive and rewarding stimuli. In this study, we recorded single cell activity patterns of nucleus accumbens (NAc) core neurons using in vivo optical imaging of calcium transients via miniature scopes. This cutting-edge imaging methodology not only allows us to record activity patterns of individual neurons but also lets us longitudinally follow these individual neurons across time and different behavioral states. Using this approach, we identified NAc core single cell ensembles that respond to experienced and/or observed aversive stimuli. Our results showed that experienced and observed aversive stimuli evoke NAc core ensemble activity that is largely positive, with a smaller subset of negative responses. The size of the NAc single cell ensemble response was greater for experienced aversive stimuli compared to observed aversive events. Our results also revealed a subpopulation within the NAc core single cell ensembles that show a bidirectional response to experienced aversive stimuli versus observed aversive stimuli (i.e., negative response to experienced and positive response to observed). These results suggest that the NAc plays a role in differentiating somatosensory experience from social observation of aversion at a single cell level. This has important implications for psychopathologies where social information processing is maladaptive, such as autism spectrum disorders.

neuroscience↗

bioRxiv2023

Prelimbic neuron calcium activity predicts perceived hedonic value across drinking solutions and ethanol dependent states in mice

AO_SCPLOWBSTRACTC_SCPLOWThe medial prefrontal cortex integrates information about salience and valence of stimuli, including rewarding solutions like alcohol and sucrose, and regulates aspects of alcohol seeking and consumption. However, our understanding of how cortical outputs encode alcohol consumption is limited. Using fiber photometry to measure calcium activity in putative prelimbic (PrL) glutamatergic projection neurons, we show similar but distinct patterns of activity during the peri-consummatory phase in response to consumption of water (non-deprived conditions), ethanol (20% v/v), or sucrose (1% w/v). PrL population activity appears to track hedonic value, as GCaMP6f signals ramped immediately preceding bouts for water, ethanol, and sucrose, and the signal scaled with presumed hedonic value, i.e., water<ethanol<sucrose. Further, using machine learning, population activity of PrL neurons prior to consumption was sufficient to predict both consumption of and distinguish between these different solutions. To assess valence encoding, we adulterated the ethanol solution with quinine, a bitter tastant. In non-dependent mice, calcium activity surrounding drinking bouts was reduced, paralleling the decreased consumption of quinine-adulterated ethanol. This effect was not present in ethanol dependent mice, suggesting altered hedonic value of the adulterated solution either due to reduced sensitivity to the aversiveness of quinine or increased sensitivity to the reinforcing value of ethanol. The global population of PrL glutamatergic neurons also display sustained GCaMP6f "up-states" that last tens to hundreds of seconds, which were longer and larger when consummatory bouts occurred. Overall, our results demonstrate a functional signature in PrL neurons that differs across solutions and is disrupted by ethanol dependence.

neuroscience↗

bioRxiv2022

Dopamine release at the time of a predicted aversive outcome causally controls the trajectory and expression of conditioned behavior

BackgroundThe inability to predict when aversive stimuli will and will not occur in is a hallmark of anxiety and stress disorders. Dopamine release in the nucleus accumbens (NAc) is sufficient and necessary for aversive learning and has been linked to both anxiety and stress disorder symptomatology. Thus, understanding how dopamine controls associative learning in response to aversive stimuli is critical to understanding the role of dopamine in behavior in health and disease. MethodsUsing an optical dopamine sensor combined with in-vivo fiber photometry in the NAc core of male and female C57BL/6J mice (N=38), we recorded dopamine responses to expected and omitted aversive outcomes during learning. We derived predictions from a theory-driven model of associative learning (Kutlu-Calipari-Schmajuk, KCS model) and tested the causality of these predictions using optogenetics. ResultsDopamine release was evoked by the predicted omission of aversive stimuli in a fashion that cannot be explained by dopamine as a reward-based prediction signal. The magnitude of the dopamine response during omissions scaled with predictions about the probability of their occurrence; however, dopamine did not track the associative value of predictive cues. Finally, we showed that the observed effects are causal to learned behavior and can only be explained by dopamine signaling the perceived saliency of predicted aversive events. ConclusionsWe elucidate the role of NAc core dopamine signaling in aversive learning in a theory-based and stimulus-specific fashion and offer potential avenues for understanding the neural mechanisms involved in anxiety and stress disorders.

neuroscience↗

bioRxiv2019

An optimized procedure for robust volitional drug intake in mice

Substance use disorder is a behavioral disorder characterized by volitional drug consumption, compulsive behavior, drug seeking, and relapse. Mouse models of substance use disorder allow for the use of molecular, genetic, and circuit level tools, which provide enormous potential for defining the underlying mechanisms of this disorder. However, the relevance of results depends entirely on the validity of the mouse models used. Self-administration models have long been considered the gold standard of preclinical addiction models, as they allow for volitional drug use, this providing strong face validity. In a series of experiments, we show that traditional mouse models of self-administration, where behavior is maintained on a fixed-ratio one schedule of reinforcement, show similar levels of responding in the presence and absence of drug delivery - demonstrating that it is impossible to determine when intake is and is not volitional. Further, when assessing inclusion criteria, we find a sex-bias in exclusion criteria where females that acquired food self-administration were eliminated when traditional criteria were applied. To address these issues, we have developed a novel mouse self-administration procedure where animals do not need to be pre-trained on food and behavior is maintained on a variable ratio schedule of reinforcement. This procedure increases rates of reinforcement behavior, increases levels of drug intake, and eliminates sex bias in inclusion criteria. Together, these data highlight a major issue with fixed-ratio models in mice that complicates subsequent analysis and provide a simple and novel approach to minimize these confounds with escalating variable-ratio schedules of reinforcement.

neuroscience↗

bioRxiv2019

A novel multidimensional reinforcement task in mice elucidates sex-specific behavioral strategies

BackgroundSex is a critical biological variable in the neuropathology of psychiatric disease, and in many cases, women represent a vulnerable population. It has been hypothesized that sex differences in neuropsychiatric disorders are manifestations of differences in basic reward processing. However, preclinical models often present rewards in isolation, ignoring that ethologically, reward seeking requires the consideration of potential aversive outcomes.\n\nMethodsWe developed a Multidimensional Cue Outcome Action Task (MCOAT) to dissociate motivated action from cue learning and valence. Mice are trained in a series of operant tasks. In phase 1, mice acquire positive and negative reinforcement in the presence of discrete discriminative stimuli. In phase 2, both discriminative stimuli are presented concurrently allowing us to parse innate behavioral strategies based on reward seeking and shock avoidance. Phase 3 is punished responding where a discriminative stimulus predicts that nose-poking for sucrose occurs concurrently with footshock, allowing for the assessment of how positive and negative outcomes are relatively valued.\n\nResultsFemales prioritize avoidance of negative outcomes over seeking positive, while males have the opposite strategy. In cases where rules are uncertain, males and females employ different strategies, with females demonstrating bias for shock avoidance.\n\nConclusionsThe MCOAT has broad utility for neuroscience research where pairing this task with recording and manipulation techniques will allow for the definition of the discrete information encoded within cellular populations. Ultimately, we show that making conclusions from unidimensional data leads to inaccurate generalizations about sex-specific behaviors that do not accurately represent ground truth.

animal behavior and cognition↗