Biology subjects

Cornish, J. L.

Publications and source records attributed to Cornish, J. L..

4 recordsLinked to original sources

bioRxiv2026

Incubation of craving for alcohol-associated cues is reduced by running-wheel exercise.

Craving - the powerful urge to seek and consume alcohol in response to alcohol-associated cues does not diminish after drinking cessation but rather is magnified throughout abstinence. This phenomenon, termed "incubation of craving", contributes to the relapsing nature of alcohol use disorder. Despite its occurrence in human populations and being well-studied in rodent models of psychostimulant drug relapse, the underlying neural mechanisms and potential treatments remain largely unexplored for alcohol-related incubation of craving. Our research seeks to meet this gap, and this particular study investigated the neural correlates of the incubation of craving for alcohol-associated cues and assessed whether exercise could prevent increased relapse propensity in rats. Male Long Evans rats were trained to lever press for an alcohol reward delivered with simultaneous presentation of a discrete cue. This response was then extinguished and reinstated by presenting the discrete cue alone when rats pressed the lever. Cue-induced reinstatement occurred either on day 1 following extinction (No Abstinence) or on day 29 (Abstinence). A third group was tested on day 29 and had 4-hour daily voluntary running wheel access throughout this abstinence period (Exercise). All rats were perfused 90 minutes following test, and relative activation across the brain was estimated by quantifying c-Fos protein immunoreactivity. The brain-wide coordination of neural activity was also mapped. We found a robust incubation of craving effect for alcohol-associated cues, which was mitigated by exercise. Immunohistochemistry revealed that the Abstinence group demonstrated higher c-Fos immunoreactivity compared to the No Abstinence group in multiple reinstatement-related brain regions. This effect was reversed in the Exercise group. Brain-wide neural mapping demonstrated that the Abstinence group had decreased modularity (groups of coordinating brain regions) compared to the no-abstinence group. Although network connectivity profile in the exercise group was different from no abstinence, we found that overall neural activation returned to a similar modularity profile of clustered regions as this condition, indicating that exercise does not attenuate the incubation of craving effect by reversing all the neural effects of abstinence. Rather, exercise may be acting upon select brain regions or pathways to exert relapse protective effects by restoring widespread interconnectivity. This is the first study to investigate neural activation in incubated alcohol-seeking, and provides supporting evidence for promoting voluntary exercise as an adjunctive treatment for relapse prevention in alcohol-use disorder.

neuroscience↗

bioRxiv2026

Neurochemical phenotype of relaxin family peptide receptor-3 (RXFP3) lateral hypothalamus/zona incerta cells

The relaxin-3/relaxin family peptide receptor 3 (RXFP3) neuropeptidergic system is emerging as a potential target for treating various neuropsychiatric diseases, particularly those involving dysregulated stress and arousal. RXFP3 is abundantly expressed in several hypothalamic nuclei, and in the zona incerta (ZI). These regions play a central role in the regulation of stress and arousal, however the function of relaxin-3/RXFP3 within these circuits is unknown. The purpose of this study was to begin characterising this function by describing the distribution and genetic signature of neurons that express RXFP3. We used RNAscope fluorescent in situ hybridisation to characterise the spatial expression pattern and neurochemical phenotype of cells expressing Rxfp3 mRNA throughout the mouse lateral hypothalamus (LH) and ZI. We found that Rxfp3 is expressed across the rostrocaudal extent of both the LH and ZI and follows a parabolic pattern of expression, peaking in more rostral areas of each nucleus. Neurochemical phenotyping of Rxfp3+ cells with Gad1, Slc17a6 (vGlut2), Pvalb, Th, and Sst showed that LH/ZI Rxfp3+ cells co-express each marker to varying extents, generally proportional to their overall abundance within each structure. Furthermore, LH/ZI Rxfp3+ cells overlapped with several known populations involved in various facets of fear learning and defensive behaviour, such as the dopaminergic A13 group, somatostatin-expressing rostral ZI neurons, and glutamatergic LH neurons. The neurochemical diversity of these neurons may reflect the overall role of both the LH and ZI as global regulators of behaviour and the role of relaxin-3/RXFP3 signalling in modulating high-vigilance states.

neuroscience↗

bioRxiv2026

Efferent projections of topographically distinct relaxin family peptide receptor-3 (RXFP3) lateral hypothalamus/zona incerta cells

Relaxin family peptide receptor-3 (RXFP3) is a ligand-activated G-protein coupled receptor and the cognate receptor for the conserved neuropeptide relaxin-3. We recently demonstrated that chemogenetically activating an RXFP3-expressing population in the lateral hypothalamus and zona incerta (LH/ZIRXFP3) induced escape-like jumping behaviour following fear conditioning, but only in a subset of mice. Given the diverse hodology of the LH and ZI, we hypothesised that LH/ZIRXFP3 cells may consist of discrete subpopulations with unique connectivity patterns that govern different aspects of defensive behaviour. To explore this possibility, we unilaterally injected small volumes of a Cre-dependent anterograde viral tracer into four distinct sites of the LH/ZI in RXFP3-Cre mice and analysed their brain-wide efferent connectivity patterns. Each injection site group produced unique projection patterns, particularly to nuclei involved in threat and defensive behaviour. Of note were strong projections from the rostral ZI and anterior LH to the lateral habenula, and projections from the intermediate and caudal ZI to the ventrolateral periaqueductal gray. By combining retrograde tracing and RNAscope fluorescent in situ hybridisation, we identified that most LH/ZIRXFP3 projections to the lateral habenula arose from a subset of vGlut2-expressing lateral hypothalamus neurons, while most projections to the ventrolateral periaqueductal gray arose from a subset of GAD1-expressing zona incerta neurons. Taken together, our results strongly suggest that LH/ZIRXFP3 cells exhibit distinct efferent projection patterns throughout the brain depending on their topographical location within these nuclei, likely reflecting the functional diversity of these neurons.

neuroscience↗

bioRxiv2021

Autonomic and respiratory components of orienting behaviors are mediated by descending pathways originating from the superior colliculus

The ability to discriminate competing, external stimuli, and initiate contextually appropriate behaviors, is a key brain function. Neurons in the deep superior colliculus (dSC) integrate multisensory inputs and activate descending projections to premotor pathways responsible for orienting and attention, behaviors which involve adjustments to respiratory and cardiovascular parameters. However, the neural pathways that subserve the physiological components of orienting are poorly understood. We report that orienting responses to optogenetic dSC stimulation are accompanied by short-latency autonomic, respiratory and electroencephalographic effects in awake rats, closely mimicking those evoked by naturalistic alerting stimuli. Physiological responses were not accompanied by detectable aversion or fear and persisted under urethane anesthesia, indicating independence from emotional stress. Moreover, autonomic responses were replicated by selective stimulation of dSC inputs to a subregion in the ventromedial medulla containing spinally-projecting premotor neurons. This putative disynaptic pathway from the dSC represents a likely substrate for autonomic components of orienting.

neuroscience↗