Biology subjects

Delevich, K.

Publications and source records attributed to Delevich, K..

8 recordsLinked to original sources

bioRxiv2026

Androgen depletion increases sensitivity to effort-related costs and alters mesoaccumbal circuit function in male mice

BackgroundAndrogen deficiency in males is associated with reduced motivation, fatigue, and decreased goal-directed behavior, yet the neural mechanisms underlying these changes remain poorly understood. Dopamine signaling within the nucleus accumbens (NAc) plays a central role in regulating effort-based decision making. Here, we tested the hypothesis that loss of testicular hormones alters mesoaccumbal dopamine function to increase sensitivity to effort-related costs. MethodsMale mice underwent orchiectomy (ORX) either before puberty onset or in adulthood. Effort-based decision making was assessed using a progressive ratio 1 closed economy (PR1-CE) task. Dopamine-related function was assessed using systemic haloperidol administration and high-performance liquid chromatography to measure dopamine and metabolites, while whole-cell recordings were used to assess intrinsic excitability of NAc spiny projection neurons (SPNs). ResultsORX increased sensitivity to effort costs, reflected by a shift toward energy-efficient responding while maintaining overall food intake. These behavioral changes were accompanied by reduced responsiveness to haloperidol. Postpubertal ORX increased dopamine content and reduced metabolite-to-dopamine ratios in the NAc, consistent with reduced dopamine turnover, whereas prepubertal ORX did not affect dopamine measures. Prepubertal ORX selectively reduced excitability of NAc core D1R+ SPNs, while postpubertal ORX increased excitability across both D1R+ and D1R- populations. ConclusionsAndrogen depletion increases effort cost sensitivity and is associated with alterations in mesoaccumbal circuit function. Although behavioral effects were similar following pre- or postpubertal ORX, distinct neurochemical and cellular adaptations were observed, suggesting developmental timing influences neural adaptations to androgen depletion. These findings provide insight into neural mechanisms linking androgen deficiency to motivational deficits.

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↗

bioRxiv2022

Sex and timing of gonadectomy relative to puberty interact to influence weight, body composition, and feeding behaviors in mice

Gonadal sex steroids are important regulators of energy balance in adult rodents, and gonadectomy (GDX) has opposing effects on weight gain in sexually mature males and females. Puberty is associated with the emergence of sex differences in weight, body composition, and feeding behaviors, yet the role of gonadal hormones at puberty remains unclear. To address this, we performed GDX or sham surgery in male and female C57Bl/6 mice at postnatal day (P)25 (prepubertal) or P60 (postpubertal) timepoints and measured weight and body composition for 35 days, after which ad libitum and operant food intake was measured using Feeding Experimentation Device 3 (FED3s) in the home cage. Consistent with previous studies, postpubertal GDX caused weight gain in females and weight loss in males and increased adiposity in both sexes. However, prepubertal GDX decreased weight gain and altered body composition across the adolescent transition (P25 to P60) in males but had no effect in females. Despite the varied effects on weight, GDX decreased food intake and motivation for food as assessed in operant tasks regardless of sex or timing of surgery relative to puberty. Our findings indicate that GDX interacts with both sex and age at surgery to influence weight, body composition, and feeding behavior. HighlightsO_LIGonadectomy had opposing effects on weight in males and females when performed in adulthood. C_LIO_LIGonadectomy performed prior to puberty decreased weight gain in males but did not affect weight gain in females. C_LIO_LIAcross sex and age at surgery, GDX decreased ad libitum food intake and reduced operant responding for food. C_LIO_LIDecreased food intake under effortful conditions was not explained by body weight in GDX mice. C_LI

animal behavior and cognition↗

bioRxiv2021

Prepubertal ovariectomy alters dorsomedial striatum indirect pathway neuron excitability and explore/exploit balance in female mice

Decision-making circuits are modulated across life stages (e.g. juvenile, adolescent, or adult)--as well as on the shorter timescale of reproductive cycles in females--to meet changing environmental and physiological demands. Ovarian hormone signaling may contribute to this flexibility by regulating neural circuits involved in adaptive decision making. Here, we examined how prepubertal ovariectomy (pOVX) influences adult performance in an odor-guided multiple-choice reversal task. During reversal learning, pOVX females exhibited a distinct pattern of errors compared to sham-operated controls. To characterize decision strategies, we fit a reinforcement learning model to trial-by-trial behavior across both the initial Discrimination and Reversal phases. Sham females showed a significant increase in the inverse temperature parameter ({beta}) during Reversal, consistent with a shift towards a more exploitative choice policy favoring high-value options. By contrast, pOVX females failed to show a phase-dependent increase in {beta}, suggesting they continued to use a more exploratory strategy. To identify a neural correlate of this behavioral phenotype, we performed whole-cell patch clamp recordings within the dorsomedial striatum (DMS), a region implicated in regulating action selection and explore/exploit choice policy. Intrinsic excitability of dopamine receptor type 2-expressing (D2R) indirect pathway spiny projection neurons (iSPNs) was significantly higher in pOVX females compared to both sham-operated and unmanipulated controls. Finally, to test whether increased D2R(+) iSPN excitability could causally contribute to the exploratory reversal phenotype, we chemogenetically activated DMS D2R(+) neurons in intact female mice. This manipulation increased exploratory choice during reversal learning, recapitulating the pattern observed following pOVX. Together, these data suggest that pubertal status may influence how females adapt their decision strategy between Discrimination and Reversal phases, potentially through long-lasting modulation of DMS iSPN intrinsic excitability.

neuroscience↗

bioRxiv2019

Sex and pubertal status influence dendritic spine density onto frontal cortiocostriatal projection neurons

In humans, nonhuman primates, and rodents, the frontal cortices exhibit grey matter thinning and dendritic spine pruning that extends late into adolescence. This protracted maturation is believed to support higher cognition but may also confer psychiatric vulnerability during adolescence. Currently, little is known about how different cell types in the frontal cortex mature or whether puberty plays a role. Here, we used mice to characterize the spatial topography and adolescent development of cross-corticostriatal (cSTR) neurons that project to the dorsomedial striatum (DMS). We found that apical spine density on cSTR neurons in the medial prefrontal cortex decreased significantly between late juvenile (P29) and young adult time points (P60), with females exhibiting higher spine density than males at both ages. Adult males castrated prior to puberty onset had higher spine density compared to sham controls. Adult females ovariectomized before puberty onset showed greater variance in spine density measures on cSTR cells compared to controls, but their mean spine density did not significantly differ from sham controls. Our findings reveal that these cSTR neurons, a subtype of the broader class of intratelencephalic-type neurons, exhibit significant sex differences and suggest that spine pruning on cSTR neurons is regulated by puberty in males.

neuroscience↗

bioRxiv2019

Choice suppression through opponent but not independent function of the striatal indirect pathway

The dorsomedial striatum (DMS) plays a key role in action selection, but little is known about how direct and indirect pathway spiny projection neurons (dSPNs and iSPNs) contribute to choice suppression in freely moving animals. Here, we used pathway-specific chemogenetic manipulation during a serial choice foraging task to test opposing predictions for iSPN function generated by two theories: 1) the select/suppress heuristic which suggests iSPN activity is required to suppress alternate choices and 2) the network-inspired Opponent Actor Learning model (OpAL) which proposes that the weighted difference of dSPN and iSPN activity determines choice. We found that chemogenetic activation, but not inhibition, of iSPNs disrupted learned suppression of nonrewarded choices, consistent with the predictions of the OpAL model. Our findings suggest that iSPNs role in stopping and freezing does not extend in a simple fashion to choice suppression. These data may provide insights critical for the successful design of interventions for addiction or other conditions in which suppression of behavior is desirable.

neuroscience↗

bioRxiv2019

Prepubertal gonadectomy reveals sex differences in approach-avoidance behavior in adult mice

Adolescence is a developmental period that is associated with physical, cognitive, and affective maturation and a time when sex biases in multiple psychiatric diseases emerge. While puberty onset marks the initiation of adolescence, it is unclear whether the pubertal rise in gonadal hormones generates sex differences in approach-avoidance behaviors that may impact psychiatric vulnerability. To examine the influence of peripubertal gonadal hormone exposure on adult behavior, we removed the gonads or performed sham surgery in male and female mice just prior to puberty onset and assessed performance in an odor-guided foraging task and anxiety-related behaviors in adulthood. We observed no significant sex differences in foraging or anxiety-related behaviors between intact adult male and female mice but found significant differences between adult male and female mice that had been gonadectomized (GDX) prior to puberty. GDX males failed to acquire the odor-guided foraging task, showed reduced locomotion, and exhibited increased anxiety-like behavior, while GDX females showed the opposite pattern of behavior. These data suggest that similar approach-avoidance phenotypes are achieved in male and female mice via different mechanisms mediated by the sex-specific hormonal milieus during pubertal maturation.

animal behavior and cognition↗

bioRxiv2018

Imaging Striatal Dopamine Release Using a Non-Genetically Encoded Near-Infrared Fluorescent Catecholamine Nanosensor

Neuromodulation plays a critical role in brain function in both health and disease. New optical tools, and their validation in biological tissues, are needed that can image neuromodulation with high spatial and temporal resolution, which will add an important new dimension of information to neuroscience research. Here, we demonstrate the use of a catecholamine nanosensor with fluorescent emission in the 1000-1300 nm near-infrared window to measure dopamine transmission in ex vivo brain slices. These near-infrared catecholamine nanosensors (nIRCats) represent a broader class of nanosensors that can be synthesized from non-covalent conjugation of single wall carbon nanotubes (SWNT) with single strand oligonucleotides. We show that nIRCats can be used to detect catecholamine efflux in brain tissue driven by both electrical stimulation or optogenetic stimulation. Spatial analysis of electrically-evoked signals revealed dynamic regions of interest approximately 2 microns in size in which transients scaled with simulation intensity. Optogenetic stimulation of dopaminergic terminals produced similar transients, whereas optogenetic stimulation of glutamatergic terminals showed no effect on nIRCat signal. Bath application of nomifensine prolonged nIRCat fluorescence signal, consistent with reuptake blockade of dopamine. We further show that the chemically synthetic molecular recognition elements of nIRCats permit measurement of dopamine dynamics in the presence of dopamine receptor agonists and antagonists. These nIRCat nanosensors may be advantageous for future use because i) they do not require virus delivery, gene delivery, or protein expression, ii) their near-infrared fluorescence facilitates imaging in optically scattering brain tissue and is compatible for use in conjunction with other optical neuroscience tool sets, iii) the broad availability of unique near-infrared colors have the potential for simultaneous detection of multiple neurochemical signals, and iv) they are compatible with pharmacology. Together, these data suggest nIRCats and other nanosensors of this class can serve as versatile new optical tools to report dynamics of extracellular neuromodulation in the brain.

neuroscience↗