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Dempsey, H.

Publications and source records attributed to Dempsey, H..

10 recordsLinked to original sources

Acute threats modulate hunger circuit dynamics to instruct avoidance behaviour

During foraging animals must balance food-seeking with predator avoidance, yet how the brain integrates sensory information relating to food and threat remains unclear. Using in vivo calcium imaging in mice, we show that hunger-sensitive AgRP neurons in the hypothalamus are rapidly inhibited by threats across a threat imminence continuum, from a low environmental risk to a high physical restraint threat, independent of fasting state. This suppression is driven by GABAergic inputs from dorsomedial hypothalamus (DMH) neurons, which increase activity during threat exposure. While AgRP population activity shows uniform inhibition, pathway-specific monitoring using axonal GCaMP reveals distinct projection patterns. For example, AgRP terminals in BNST and LH decrease activity to both threat and food, while threats increased AgRP axonal activity in the PVN. Furthermore, location-specific optogenetic inhibition of AgRP neurons conditions spatial avoidance, mimicking a threat-induced defensive behavioural responses. These findings reveal a hypothalamic circuit where DMH GABA neurons suppress AgRP activity in response to external threats, prioritising avoidance over food-seeking to optimise adaptive behavioural responses during foraging.

neuroscience↗

Sex differences in neural circuits driving binge drinking: A female-specific role for an amygdalo-striatal pathway

BackgroundRates of binge drinking have converged significantly between the sexes over recent decades, driven by increased rates of alcohol misuse in women. However, understanding of fundamental circuitry and neurobiology driving alcohol use in females, or how this may differ from male subjects remains underexplored. MethodsWe quantified c-Fos expression across 40 brain regions in alcohol naive, alcohol anticipating and binge drinking male and female mice. In vivo fiber photometry examined sex differences in basolateral amygdala (BLA) activity changes to alcohol intake. Chemogenetic BLA inhibition investigated a functional role in binge drinking. We then assessed sex differences in BLA efferent projection activation following binge drinking. Finally, we functionally interrogated the BLA to nucleus accumbens core (AcbC) projection in binge drinking. ResultsBinge drinking reduced network modularity (number of communities with similar activation patterns) in both sexes relative to alcohol naive and anticipating same-sex counterparts. Female binge drinking mice had increased BLA c-Fos expression compared to female naive and male binge drinking counterparts. In vivo fiber photometry revealed greater and more prolonged BLA responsivity at the onset of alcohol intake in females. Global BLA inhibition reduced reward intake in both sexes. However, the BLA to AcbC projection was preferentially activated in female binge drinking mice, and inhibition of this pathway reduced binge alcohol intake exclusively in females. ConclusionsWe identified sex differences in the neural circuits engaged in binge drinking, highlighting the BLA to AcbC projection may in part underpin sex differences in alcohol misuse. This provides further evidence of distinct neurobiological drivers of alcohol-related behaviors between the sexes.

neuroscience↗

Hunger alters approach-avoidance behaviours differently in male and female mice

BackgroundThe decision about whether to approach or avoid a reward while under threat requires balancing competing demands. Sex-specific prioritisations (e.g. mating, maternal care), or generalised prioritisations (e.g. feeding, drinking, sleeping) may differently influence approach-avoidance behaviours based on the level of "risk" and homeostatic need state of the organism. However, given known sex differences in key aspects that may influence this behaviour, direct comparison of how male and female mice make decisions to approach or avoid a dangerous area while in a fasted state have yet to be conducted. MethodsWe conducted several approach-avoidance tasks with varied levels of risk and reward in male and female mice that were either fasted or sated (fed). Mice underwent a light-dark box, elevated plus maze, baited large open field and runway task to assess their approach and avoidance behaviour. ResultIn the light-dark box and elevated plus maze, when no reward was available, fasted female mice showed greater approach behaviours than male counterparts. In the baited large open field, when reward was available, both sexes showed increased approach behaviours when fasted. However, when sated, male mice conversely showed greater approach behaviours compared to sated female mice. In the runway task, while sated mice failed to learn, fasted male mice inhibited their reward consumption in response to increased shock intensity; however, fasted female mice were resistant to increased shock intensity. ConclusionsOur study identifies sex differences in decision making behaviour in mice based on satiety state across a number of approach-avoidance tasks. We highlight several nuances of these differences based on reward availability and punishment intensity. These results shine a lens on fundamental differences between the sexes in innate, survival driven behaviours that should be taken into account for future studies. Plain English summaryEveryday decision making is often accompanied by conflict - whether we make the most appropriate decision or not can be influenced by both internal and external factors. Environmental threats and physiological pressures, such as hunger, can influence decision-making processes skewing the risk/reward ratio, yet how this may differ between the sexes has not been explored in detail. Here we used several tasks that assess decision-making in mice while manipulating the levels of risk or reward. Our findings show fasted female mice are more willing to engage in "risky" behaviour compared to fed female mice when risk levels were low, and no food reward was available. However, when a food reward was available, but risk levels were low, both male and female fasted mice were more likely to engage in risky behaviour compared to fed mice. Finally, when risk levels were high and food reward was available, fasted female mice continued to engage in risky behaviour, while male fasted mice were not. Together our study identifies nuanced sex differences in how male and female mice make decisions influenced by both physiological (hunger) and environmental threats and highlight the importance of understanding fundamental differences between the sexes in behaviour. Highlights- Fasted female mice showed greater approach behaviours compared to fasted male counterparts in tasks without reward availability. - Fasted mice of both sexes displayed greater approach behaviours when a reward was available, compared to sated controls. - Fasted male mice inhibited reward consumption under increased shock intensity, whereas fasted female mice were resistant to mild foot shock.

neuroscience↗

Metabolic sensing in AgRP regulates sucrose preference and dopamine release in the nucleus accumbens

Hunger increases the motivation for calorie consumption, often at the expense of low taste appeal. However, the neural mechanisms integrating calorie-sensing with increased motivation for calorie consumption remain unknown. Agouti-related peptide neurons in the arcuate nucleus of the hypothalamus sense hunger, and the ingestion of caloric solutions promote dopamine release in the absence of sweet taste perception. Therefore, we hypothesized that metabolic-sensing of hunger by AgRP neurons would be essential to promote dopamine release in the nucleus accumbens in response to caloric, but not non-caloric solutions. Moreover, we examined whether metabolic sensing in AgRP neurons affected taste preference to bitter solutions under conditions of energy need. Here we show that impaired metabolic sensing in AgRP neurons attenuated nucleus accumbens dopamine release in response to sucrose, but not saccharin, consumption. Further, metabolic sensing in AgRP neurons was essential to distinguish nucleus accumbens dopamine response to sucrose consumption when compared with saccharin. Under conditions of hunger, metabolic sensing in AgRP neurons increased the preference of sucrose solutions laced with the bitter tastant, quinine, to ensure calorie consumption whereas mice with impaired metabolic sensing in AgRP neurons maintained a strong aversion to sucrose/quinine solutions despite ongoing hunger. In conclusion, we demonstrate normal metabolic sensing in AgRP neurons drives the preference for calorie consumption, primarily when needed, by engaging dopamine release in nucleus accumbens.

neuroscience↗

Ghrelin signalling in AgRP neurons links metabolic state to the sensory regulation of AgRP neural activity.

ObjectiveThe sensory detection of food and food cues suppresses Agouti related peptide (AgRP) neuronal activity prior to consumption with greatest suppression in response to high caloric food or energy need. Although external sensory cues regulate AgRP neuronal activity, the interoceptive mechanisms priming an appropriate AgRP neural response to sensory information of caloric availability remain unexplored. Since hunger increases plasma ghrelin, we hypothesized that ghrelin receptor (GHSR) signalling on AgRP neurons is a key interoceptive mechanism integrating energy need with external sensory cues predicting caloric availability. MethodsWe used in vivo photometry to measure the effects of ghrelin administration or fasting on AgRP neural activity with GCaMP6s and dopamine release in the nucleus accumbens with GRAB-DA in mice lacking ghrelin receptors in AgRP neurons. ResultsThe deletion of GHSR on AgRP neurons prevented ghrelin-induced food intake, motivation and AgRP activity. The presentation of food (peanut butter pellet) or a wooden dowel suppressed AgRP activity in fasted WT but not mice lacking GHSRs in AgRP neurons. Similarly, peanut butter and a wooden dowel increased dopamine release in the nucleus accumbens after ip ghrelin injection in WT but not mice lacking GHSRs in AgRP neurons. No difference in dopamine release was observed in fasted mice. Finally, ip ghrelin administration did not directly increase dopamine neural activity in the ventral tegmental area. ConclusionsOur results suggest that AgRP GHSRs integrate an interoceptive state of energy need with external sensory information to produce an optimal change in AgRP neural activity. Thus, ghrelin signalling on AgRP neurons is more than just a feedback signal to increase AgRP activity during hunger.

neuroscience↗

Temporal regulation of AgRP neurons mediates context-induced feeding

An environment can have a powerful influence over appetite and feeding behaviour. For example, an environmental context, which reliably predicts food, will increase the appetitive food drive to the same environment context. Interestingly, mice are required to be hungry to develop such a context-induced feeding (CIF) response, suggesting the neural circuits sensitive to hunger play an important role to associate an internal energy state with a particular environment context. Hunger-sensing Agouti related peptide (AgRP) neurons are activated by circulating signals of energy deficit and reset to a silenced state by gut feedback mechanisms following food consumption. We hypothesised that AgRP neurons are both necessary and sufficient to drive CIF in the absence of hunger. While fasting increased CIF, chemogenetic inhibition of AgRP neurons during context acquisition prevented this effect. Intriguingly, chemogenetic activation of AgRP neurons during context acquisition did not increase CIF, suggesting precise temporal firing properties may be required. Indeed, photostimulation of AgRP neurons, only during context exposure (ON-OFF in context), increased CIF. Moreover, AgRP photostimulation prior to context exposure, coupled with the termination of photostimulation in the context in the absence of food consumption, was sufficient to drive a subsequent CIF. Our results suggest that AgRP neurons regulate the acquisition of CIF when the temporal firing properties are matched to context exposure. These results further highlight that acute AgRP inhibition is a salient neural event underscoring the effect of hunger on associative learning.

neuroscience↗

Hunger signalling in the olfactory bulb primes exploration, food-seeking and peripheral metabolism.

Growing evidence highlights a complex interaction between olfaction and metabolism with impaired olfactory function observed in obesity and increased olfactory sensitivity during hunger. The mechanisms linking metabolic state and olfaction remain unknown, but increased accessibility of hormones, such as ghrelin, and the diverse expression of hormone receptors such as those for ghrelin (GHSRs) in the olfactory system suggests an underappreciated neuroendocrine role. Here, we examined the hypothesis that GHSRs in the olfactory bulb (OB) link hunger with olfactory sensitivity to influence foraging behaviours and metabolism. Selective deletion of OBGHSRs in adult male mice was achieved with adeno-associated viral expression of cre-recombinase in the OB of floxed-Ghsr mice. OBGHSR deletion significantly affected olfactory discrimination and habituation to both food and pheromone odours, with greatest effect under fasted conditions. Anxiety-like and depression-like behaviour was significantly greater after OBGHSR deletion using 3 independent anxiety behavioural tasks and testing for anhedonia, whereas exploratory behaviour was reduced. No effect on spatial navigation and memory was observed. Although OBGHSR deletion did not affect cumulative food intake, it significantly impacted feeding behaviour as evidenced by altered bout number and duration. Moreover, food-finding after fasting or ip ghrelin was attenuated. Intriguingly, OBGHSR deletion caused an increase in body weight and fat mass, spared fat utilisation on a chow diet and impaired glucose metabolism indicating metabolic dysfunction. We conclude that OBGHSRs maintain olfactory sensitivity, particularly during hunger, and facilitate behavioural adaptations that optimise food-seeking in anxiogenic environments, priming metabolic pathways in preparation for food consumption.

neuroscience↗

Rapid, automated and experimenter-free assessment of cognitive flexibility reveals learning impairments following recovery from activity-based anorexia in female rats

Anorexia nervosa (AN) has among the highest mortality rates of any psychiatric disorder and is characterised by cognitive inflexibility that persists after weight recovery and contributes to the low rates of recovery. What remains unknown is whether cognitive inflexibility predisposes individuals to AN, a question that is difficult to determine from human studies. Our previous work using the most well-established animal model of AN, known as activity-based anorexia (ABA) identified a neurobiological link between cognitive inflexibility and susceptibility to pathological weight loss in female rats. However, testing flexible learning prior to exposure to ABA in the same animals has been thus far impossible due to the length of training required and the necessity of daily handling, which can itself influence the development of ABA. Here we describe experiments that validate and optimise the first fully-automated and experimenter-free touchscreen cognitive testing system for rats (n=20) and use this novel system to examine the reciprocal links between reversal learning (an assay of cognitive flexibility) and weight loss in the ABA model (n=60). Firstly, we show substantially reduced testing time and increased throughput compared to conventional touchscreen testing methods because animals engage in test sessions at their own direction and can complete multiple sessions per day without experimenter involvement. We also show that, contrary to expectations, cognitive inflexibility does not predispose rats to pathological weight loss in ABA but instead that rats subsequently susceptible to weight loss performed better on the reversal learning task. Intriguingly, we show reciprocal links between ABA exposure and cognitive flexibility, with ABA exposed (but weight recovered) rats performing much worse that ABA naive rats on the reversal learning task. On the other hand, animals that had been trained on reversal learning were better able to resist weight loss upon subsequent exposure to the ABA model. We also uncovered some stable behavioural differences between ABA susceptible versus resistant rats during touchscreen test sessions using machine learning tools that highlight possible predictors of anorectic phenotypes. These findings shed new light on the relationship between cognitive inflexibility and pathological weight loss and provide a robust target for future studies using the ABA model to investigate potential novel pharmacotherapies for AN.

animal behavior and cognition↗

Identification of a stress-sensitive anorexigenic neurocircuit from medial prefrontal cortex to lateral hypothalamus in humans and mice

By modeling neural network dynamics related to homeostatic state and BMI, we identified a novel pathway projecting from the medial prefrontal cortex (mPFC) to the lateral hypothalamus (LH) in humans. We then assessed the physiological role and dissected the function of this mPFC-LH circuit in mice. In vivo recordings of population calcium activity revealed that this glutamatergic mPFC-LH pathway is activated in response to acute stressors and inhibited during food consumption, suggesting a role in stress-related control over food intake. Consistent with this role, inhibition of this circuit increased feeding and sucrose seeking during mild stressors, but not under non-stressful conditions. Finally, chemogenetic or optogenetic activation of the mPFC-LH pathway is sufficient to suppress food intake and sucrose-seeking in mice. These studies identify a glutamatergic mPFC-LH as a novel stress-sensitive anorexigenic neural pathway involved in the cortical control of food intake.

neuroscience↗

Glucose-sensing in AgRP neurons integrates homeostatic energy state with dopamine signalling in the striatum.

Hunger increases the motivation of an organism to seek out and consume highly palatable energy dense foods. While hunger-sensing Agouti-related peptide (AgRP) neurons influence this process, whether metabolic detection of homeostatic state via metabolic sensing in AgRP neurons potentiates motivation through the midbrain dopamine system is unexplored. Here, we used the AgRP-specific deletion of carnitine acetyltransferase (Crat), a metabolic enzyme regulating glucose and fatty acid oxidation, as a model of impaired metabolic-sensing in AgRP neurons. We then tested the hypothesis that appropriate metabolic-sensing in AgRP neurons is required to increase food reward motivation by modulating accumbal or striatal dopamine release. Electrophysiological studies confirm that Crat deletion in AgRP neurons (KO) impairs normal ex vivo glucose-sensing, and in vivo photometry experiments show that AgRP neurons in KO mice do not exhibit normal responses to repeated palatable food presentation and consumption, highlighting that this model is appropriate to test the hypothesis. Fiber photometry experiments, using the dopamine sensor GRAB-DA, revealed that impaired metabolic-sensing reduces acute dopamine release (seconds) in the nucleus accumbens, but not the dorsal striatum, to palatable food consumption and during operant responding. Positron electron tomography (PET) methods indicated that impaired metabolic-sensing in AgRP neurons suppressed radiolabelled 18F-fDOPA accumulation after [~]30 minutes in the dorsal striatum but not the ventral striatum, suggesting a role for AgRP neurons to restrict a long term post-ingestive dopamine response in the dorsal striatum. Finally, impaired metabolic-sensing in AgRP neurons suppresses motivated operant responding for sucrose rewards. Notably, these behavioural effects are potentiated in the hungry state and therefore highlight that metabolic-sensing in AgRP neurons is required for the appropriate temporal integration and transmission of homeostatic hunger-sensing to dopamine signalling in the striatum.

neuroscience↗