Biology subjects

Kravitz, A. V.

Publications and source records attributed to Kravitz, A. V..

13 recordsLinked to original sources

bioRxiv2026

N-Methyl-D-Aspartate receptors control in vivo striatal calcium and the updating of action policy

Animals must execute learned behaviors and update them when outcomes change, yet the neural substrates controlling this phenomenon are not fully understood. Here, we show that N-Methyl-D-Aspartate Receptors (NMDARs) in the dorsomedial striatum are necessary for learning from previously rewarded actions. Moreover, blocking of striatal NMDARs almost fully abolished striatal calcium dynamics, but not action potential activity, suggesting a unique function of NMDAR-driven striatal calcium activity in updating action policy.

neuroscience↗

bioRxiv2026

Ventral pallidal GABAergic neurons control hedonic feeding and obesity

Food intake is governed by two interacting drives. The homeostatic hunger drive regulates food intake to fulfill caloric needs while the hedonic drive promotes intake of palatable foods outside of caloric need. It is unclear which neural substrates can control the hedonic drive and thereby reduce overeating of palatable foods and associated obesity. Here, we show that ventral pallidal GABAergic neurons (VPGABA) preferentially control hedonic feeding and are necessary for diet-induced obesity in mice. Stimulating VPGABA neurons drove robust consumption of high-fat diet and liquids, but not regular laboratory chow. Despite driving intake of palatable foods, VPGABA neurons are relatively insensitive to homeostatic signals - they express few hunger-hormone receptors and are not activated by ghrelin administration or fasting. Single-cell calcium imaging revealed stronger engagement of VPGABA neurons during long vs short feeding bouts, suggesting control over bout duration, which has been linked to palatability. This was confirmed with closed-loop optogenetic stimulation. Finally, taCasp3-mediated ablation of VPGABA neurons reduced intake of palatable liquids and blocked high-fat diet-induced obesity without impacting homeostatic feeding. Together, these findings establish VPGABA neurons as a neural population that preferentially controls hedonic over homeostatic feeding and can be leveraged to block obesity in mice.

neuroscience↗

bioRxiv2026

A Preoptic Neuronal Population Regulates Energy Expenditure and Balance

Maintaining energy balance requires coordination between food intake and energy expenditure, yet the neural pathways that regulate energy expenditure remain unclear. This study identifies kappa opioid receptor-expressing neurons in the preoptic area of the hypothalamus as a key regulator of whole-body metabolism. Using mouse models combined with fiber photometry, chemogenetic activation and inhibition, and chronic disruption of synaptic output, the results show that activity of these neurons follows daily pattern, are suppressed during feeding, and their inhibition acutely increases energy expenditure, body temperature, and activity levels. Long-term inhibition of this population produces sustained weight loss, selective reduction of white fat, preservation of lean mass and brown fat, and improved glucose tolerance even during high-fat feeding. These findings reveal a previously unrecognized circuit that links metabolic state with daily timing cues and suggest that targeting this neuronal population may offer new strategies for treating obesity and related metabolic disorders.

neuroscience↗

bioRxiv2026

Sex differences in exploration-exploitation strategies during home-cage decision making

The exploration-exploitation trade-off refers to the conflict between using known strategies that reliably yield reward (exploitation) and sampling uncertain options that might yield better outcomes (exploration). Dysregulation of this balance is implicated in neuropsychiatric disease, and while sex differences in this balance have been described, the biological bases remain unclear. To quantify sex differences in this trade-off, we tested mice (n=74 male, 62 female) on four home-cage based foraging tasks with an operant pellet dispensing device, Feeding Experimentation Device 3 (FED3). Mice completed the tasks continuously over multiple days and the tasks were their only source of food. Across multiple tasks, males showed higher win-stay behaviour than females, indicating greater exploitation of previously rewarded actions, an effect that was modest in size but highly significant. Power analyses revealed that >30 mice per sex were needed to detect these modest but significant sex differences with 80% power. No consistent sex differences were observed in pellet intake, suggesting that differences in exploitation did not reflect differences in hunger drive or demand for pellets. Exploitation is a more efficient strategy when environmental parameters are fixed, while exploration can be more advantageous when parameters such as reward locations are changing and uncertain. We tested this idea by re-running our mice in a probabilistic foraging task, where actions led to uncertain probabilities of reward. While males continued to show higher levels of win-stay behaviour on this task, this no longer led to increases in accuracy. Behavioural modelling also supported this framework, demonstrating that stronger win-stay behaviour was most advantageous in deterministic models, and less advantageous in probabilistic models. Together, our findings demonstrate that male and female mice have small but significant differences in their exploration-exploitation balance, which leads to more accurate foraging in certain, but not uncertain, environments.

neuroscience↗

bioRxiv2025

Reduced SK channel control of mesolimbic dopamine neuron firing drives reward seeking adaptations in chronic pain

Patients with chronic neuropathic pain typically experience affective symptoms that drive reduced quality of life and negatively impact pain management. Mesolimbic dopamine is necessary for reward valuation and learning, and the existence of a hypodopaminergic state has been proposed to underlie these affective symptoms of chronic pain. However, direct functional evidence for this hypodopaminergic state is lacking, and the mechanisms underlying its emergence over the acute to chronic pain transition are unknown. Here, we find a selective deficit in the ability of mesolimbic dopamine neurons to sustain burst firing, which is apparent uniquely at chronic timepoints following neuropathic injury. As a result, animals are unable to sustain effortful pursuit of rewards under conditions of high effort or time costs. Convergent biophysical modeling and experimental electrophysiology establish that in a spared nerve injury (SNI) model of chronic neuropathic pain, calcium-activated, small-conductance potassium (SK) channel function is impaired, resulting in lower peak firing and earlier entry into depolarization block of mesolimbic dopamine neurons. Critically, dopamine dependent reward learning, formation of cue-reward associations and locomotor activity remain intact, arguing against the interpretation of a generalized hypodopaminergic state. These results elucidate a circuit-level basis for selective motivational deficits emerging in chronic neuropathic pain.

neuroscience↗

bioRxiv2024

A simple action reduces food intake and obesity in mice

Diets that are high in fat cause over-eating and weight gain in multiple species of animals, suggesting that high dietary fat is sufficient to cause obesity. However, high-fat diets are typically provided freely to animals in obesity experiments, so it remains unclear if high-fat diets would still cause obesity if they required more effort to obtain. We hypothesized that unrestricted and easy access is necessary for high-fat diet induced over-eating, and the corollary that requiring mice to perform small amounts of work to obtain high-fat diet would reduce high-fat diet intake and associated weight gain. To test this hypothesis, we developed a novel home-cage based feeding device that either provided high-fat diet freely, or after mice poked their noses into a port one time - a simple action that is easy for them to do. We tested the effect of this intervention for six weeks, with mice receiving all daily calories from high-fat diet, modifying only how they accessed it. Requiring mice to nose-poke to access high-fat diet reduced intake and nearly completely prevented the development of obesity. In follow up experiments, we observed a similar phenomenon in mice responding for low-fat grain-based pellets that do not induce obesity, suggesting a general mechanism whereby animals engage with and consume more food when it is freely available vs. when it requires a simple action to obtain. We conclude that unrestricted access to food promotes overeating, and that a simple action such as a nose-poke can reduce over-eating and weight gain in mice. This may have implications for why over-eating and obesity are common in modern food environments, which are often characterized by easy access to low-cost unhealthy foods.

animal behavior and cognition↗

bioRxiv2023

Impact of delta9-tetrahydrocannabinol and oxycodone co-administration on measures of antinociception, dependence, circadian activity, and reward in mice

Oxycodone is commonly prescribed for moderate to severe pain disorders. While efficacious, long-term use can result in tolerance, physical dependence, and the development of opioid use disorder. Cannabis and its derivatives such as {Delta}9-Tetrahydrocannabinol ({Delta}9-THC) have been reported to enhance oxycodone analgesia in animal models and in humans. However, it remains unclear if {Delta}9-THC may facilitate unwanted aspects of oxycodone intake, such as tolerance, dependence, and reward at analgesic doses. This study sought to evaluate the impact of co-administration of {Delta}9-THC and oxycodone across behavioral measures related to antinociception, dependence, circadian activity, and reward in both male and female mice. Oxycodone and {Delta}9-THC produced dose-dependent antinociceptive effects in the hotplate assay that were similar between sexes. Repeated treatment (twice daily for 5 days) resulted in antinociceptive tolerance. Combination treatment of oxycodone and {Delta}9-THC produced a greater antinociceptive effect than either administered alone, and delayed the development of antinociceptive tolerance. Repeated treatment with oxycodone produced physical dependence and alterations in circadian activity, neither of which were exacerbated by co-treatment with {Delta}9-THC. Combination treatment of oxycodone and {Delta}9-THC produced CPP when co-administered at doses that did not produce preference when administered alone. These data indicate that {Delta}9-THC may facilitate oxycodone-induced antinociception without augmenting certain unwanted features of opioid intake (e.g. dependence, circadian rhythm alterations). However, our findings also indicate that {Delta}9-THC may facilitate rewarding properties of oxycodone at therapeutically relevant doses which warrant consideration when evaluating this combination for its potential therapeutic utility.

neuroscience↗

bioRxiv2022

Glutamatergic Supramammillary Nucleus Neurons Promote Active Coping to Stress

Threat-response neural circuits are conserved across species and play roles in normal behavior and psychiatric diseases. Maladaptive changes in these neural circuits contribute to stress, mood, and anxiety disorders. Active coping in response to stressors is a psychosocial factor associated with resilience against stress-induced mood and anxiety disorders. The neural circuitry underlying active coping is poorly understood, but the functioning of these circuits could be key for overcoming anxiety and related disorders. The supramammillary nucleus (SuM) has been suggested to be engaged by threat. SuM has many projections and contains a poorly understood diversity of populations. We identified a unique population of glutamatergic SuM neurons (SuMVGLUT2+::POA) based on projection to the preoptic area of the hypothalamus (POA) and found SuMVGLUT2+::POA neurons have extensive arborizations. SuMVGLUT2+::POA neurons project to brain areas that mediate various features of the stress and threat responses including the paraventricular nucleus thalamus (PVT), periaqueductal gray (PAG), and the habenula (Hb). Thus, SuMVGLUT2+::POA neurons are positioned as a hub, connecting to areas implicated in regulating stress responses. Here we report SuMVGLUT2+::POA neurons are recruited by diverse threatening stressors, and recruitment of SuMVGLUT2+::POA neurons correlated with active coping behaviors. We found that selective photoactivation of the SuMVGLUT2+::POA population drove aversion but not anxiety like behaviors. Activation of SuMVGLUT2+::POA neurons in the absence of acute stressors evoked active coping like behaviors and drove instrumental behavior (selective port activations) (Figure 6). Also, activation of SuMVGLUT2+::POA neurons was sufficient to convert passive coping strategies to active behaviors during acute stress. In contrast, we found activation of GABAergic (VGAT+) SuM neurons (SuMVGAT+) neurons did not alter drive aversion or active coping, but termination of photostimulation was followed by increased mobility in the forced swim test. These findings establish a new node in stress response circuitry that has projections to many brain areas, evokes flexible active coping behaviors, and offers new opportunities for furthering our neurobiological understanding of stress. O_FIG O_LINKSMALLFIG WIDTH=134 HEIGHT=200 SRC="FIGDIR/small/507167v4_fig6.gif" ALT="Figure 6"> View larger version (30K): org.highwire.dtl.DTLVardef@717f84org.highwire.dtl.DTLVardef@16ad323org.highwire.dtl.DTLVardef@4ba5b6org.highwire.dtl.DTLVardef@6c811e_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOFigure 6.C_FLOATNO SuMVGLUT2+::POA neurons can drive instrumental action-outcome operant behavior (A) Schematic of injection and implant in VGLUT2+ Cre mice and paradigm of testing in 10-minute trials with four days before a progressive ratio (PR) trial on day five. (B) Illustration of the testing paradigm and set up. 10 Hz photostimulation was applied during the trials. Activation of the active port triggered the house light and paused stimulation for 10 seconds. Also shown is the progressive ratio used with number of required port activations per reward on vertical axis and reward number on the horizontal. (C) Cre+ mice (n=11) activated the active port triggering significantly (****p<0.0001) more pauses in stimulation than Cre- mice (n=11) mice on all four days of testing. (D) Cre+ mice activated the port significantly (****p<0.0001, ***p<0.001) more than the Cre- mice on all four trials. (E) The time to first activation of the active port was significantly (*p=0.046) different during the first trial, and Cre+ mice activated the active port significantly (**p<0.01, **p<0.01, **p=0.034) faster on subsequent trials. (F) On the fifth day after four 10-minute trials, mice were tested for 30 minutes using a progressive ratio. Cre+ performed significantly (****p<0.001) more active port activations than Cre- mice and activated the inactive port significantly more (**p=0.001) times. Cre+ mice also triggered significantly (****p<0.001) more pauses in photostimulation than Cre- mice. (G) Individual data for a representative (n=7) cohort of Cre+ mice showing cumulative active port activations as a function of time during the progressive ratio test show on-going engagement of the active port throughout the 30-minute trial. (H) The cumulative pauses in photostimulation (rewards) earned as a function of time during the progressive ratio trial are shown for individual Cre+ mice. Mice earned between 7 and 11 pause rewards during the trial. All data plotted as means {+/-}SEM. C_FIG

neuroscience↗

bioRxiv2022

Dopaminergic innervation at the central nucleus of the amygdala reveals distinct topographically and functionally segregated regions

The central nucleus of the amygdala (CeA) is involved in the expression of fear and has been implicated in several anxiety disorders. Anatomically, it is divided in a medial (CeM), a lateral (CeL) and a capsular division (CeC). The CeA is densely innervated by dopaminergic projections that originate in the ventral periaqueductal gray/dorsal raphe (vPAG/DR) and the ventral tegmental area/substantia nigra compacta (VTA/SNc). However, it is unknown if DA exerts a homogenous control over the CeA or, conversely, if different parts of the CeA are regulated in a distinct manner. Here, we performed a neuroanatomical and functional analysis of the mouse CeA and revealed that dopaminergic innervations arriving from the PAG/DR and the VTA/SNc constitute distinct, non-overlapping pathways that differ in their expression of dopamine transporter. By quantifying the distribution of DAergic fibers and the origin of the innervation, we identified two regions in the CeL: a frontal region innervated by both the VTA/SNc and the vPAG/DR, and a caudal region innervated only by the vPAG/DR; and three regions in the CeC: a fronto-dorsal region innervated only by the VTA/SNc, a fronto-ventral region with sparse DAergic innervation, and a caudal region with low innervation from the vPAG/DR. In addition, we found that each region displays a unique pattern of cFos activation after the administration of cocaine, SKF 38393, quinpirole or haloperidol, demonstrating that the regions identified here are functionally distinct from each other. In summary, this analysis reveals unique properties of the DAergic pathways innervating the CeA, and distinguishes six topographically segregated and functionally distinct regions in the CeA. This unanticipated level of functional heterogeneity calls for more precise anatomical specificity in future functional studies of the CeA.

neuroscience↗

bioRxiv2022

Oral oxycodone self-administration leads to features of opioid addiction in male and female mice

Use of prescription opioids, particularly oxycodone is an initiating factor driving the current opioid epidemic. There are several challenges with modeling oxycodone abuse. First, prescription opioids including oxycodone are orally self-administered and have different pharmacokinetics and dynamics than morphine or fentanyl which have been more commonly used in rodent research. This oral route of administration determines the pharmacokinetic profile, which then influences the establishment of drug-reinforcement associations in animals. Moreover, the pattern of intake and the environment in which addictive drugs are self-administered are critical determinants of the levels of drug intake, of behavioral sensitization, and of propensity to relapse behavior. These are all important considerations when modeling prescription opioid use, which is characterized by continuous drug access in familiar environments. Thus, to model features of prescription opioid use and the transition to abuse, we designed an oral, homecage-based oxycodone self-administration paradigm. Mice voluntarily self-administer oxycodone in this paradigm without any taste modification such as sweeteners, and the majority exhibit preference for oxycodone, escalation of intake, physical signs of dependence, and reinstatement of seeking after withdrawal. In addition, a subset of animals demonstrate drug taking that is resistant to aversive consequences. This model is therefore translationally relevant and useful for studying the neurobiological substrates of prescription opioid abuse.

neuroscience↗

bioRxiv2022

Enhanced food motivation in obese mice is controlled by D1R expressing spiny projection neurons in the nucleus accumbens.

Obesity is a chronic relapsing disorder that is caused by an excess of caloric intake relative to energy expenditure. In addition to homeostatic feeding mechanisms, there is growing recognition of the involvement of food reward and motivation in the development of obesity. However, it remains unclear how brain circuits that control food reward and motivation are altered in obese animals. Here, we tested the hypothesis that signaling through pro-motivational circuits in the core of the nucleus accumbens (NAc) is enhanced in the obese state, leading to invigoration of food seeking. Using a novel behavioral assay that quantifies physical work during food seeking, we confirmed that obese mice work harder than lean mice to obtain food, consistent with an increase in the relative reinforcing value of food in the obese state. To explain this behavioral finding, we recorded neural activity in the NAc core with both in vivo electrophysiology and cell-type specific calcium fiber photometry. Here we observed greater activation of D1-receptor expressing NAc spiny projection neurons (NAc D1SPNs) during food seeking in obese mice relative to lean mice. With ex vivo slice physiology we identified both pre- and post-synaptic mechanisms that contribute to this enhancement in NAc D1SPN activity in obese mice. Finally, blocking synaptic transmission from D1SPNs decreased physical work during food seeking and attenuated high-fat diet-induced weight gain. These experiments demonstrate that obesity is associated with a selective increase in the activity of D1SPNs during food seeking, which enhances the vigor of food seeking. This work also establishes the necessity of D1SPNs in the development of diet-induced obesity, establishing these neurons as a potential therapeutic target for preventing obesity.

neuroscience↗

bioRxiv2021

Modeling features of addiction with an oral oxycodone self-administration paradigm

Prescription opioid use is an initiating factor driving the current opioid epidemic. There are several challenges with modeling prescription opioid addiction. First, prescription opioids such as oxycodone are orally self-administered and have different pharmacokinetics and dynamics than morphine or fentanyl. This oral route of administration determines the pharmacokinetic profile, which is critical for establishing reliable drug-reinforcement associations in animals. Moreover, the pattern of intake and environment in which addictive drugs are self-administered intake are critical determinants of the levels of drug intake, sensitization and relapse behavior. This is an important consideration with prescription opioid use, which is characterized by continuous drug access in familiar environments. Thus, to model features of prescription opioid use and the transition to abuse, we present an oral oxycodone self-administration paradigm that is administered in the home cage. Mice voluntarily self-administer oxycodone in this paradigm without any taste modification such as sweeteners, and exhibit preference for oxycodone, escalation of intake, physical signs of dependence, reinstatement of seeking after withdrawal, and a subset of animals demonstrate drug taking that is resistant to aversive consequences. This model could be useful for studying the neurobiological substrates specifically relevant to prescription opioid abuse.

neuroscience↗

bioRxiv2019

A role for the locus coeruleus in the modulation of feeding

Recent data suggest that LC-NE neurons play a role in fear-induced suppression of feeding, but their endogenous activity in naturally behaving animals has not been explored. We found that endogenous activity of LC-NE neurons was enhanced during food approach and suppressed during food consumption, and that these food-evoked LC-NE responses were attenuated in sated mice. Interestingly, visual-evoked LC-NE activity was also attenuated in sated mice, demonstrating that internal satiety state modulates LC-NE encoding of multiple behavioral states. We also found that food intake could be attenuated by brief or longer durations of LC-NE activation. Lastly, we demonstrated that activation of LC neurons suppresses feeding and enhances avoidance and anxiety-like responding through a projection to the lateral hypothalamus. Collectively, our data suggest that LC-NE neurons modulate feeding by integrating both external cues (e.g., anxiogenic environmental cues) and internal drives (e.g., nutritional state).

neuroscience↗