Biology subjects

Perry, C. J.

Publications and source records attributed to Perry, C. J..

10 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↗

bioRxiv2025

Perturbational single-cell profiling of patient tumors defines lineage- and context-specific programs of innate immune resistance

AbstractDespite promise in preclinical models, most immuno-oncology drug candidates fail in clinical trials. These failures reflect limitations in our ability to directly model the response of human tumor and immune cells to immunotherapies. To address this gap and test the effect of innate immune agonists, we developed PERCEPT, an approach that uses ex vivo perturbational single-cell RNA sequencing to compare the response of immunomodulatory treatments with unstimulated controls directly in patient samples. Using PERCEPT, we tested cytokines and innate immune agonists in melanoma and Merkel cell carcinoma (MCC) and identified the dsRNA mimetic, RIG-I agonist, Stem Loop RNA (SLR) 14 as a powerful inducer of anti-viral states and enhancer of T cell activation. We compared transcriptional responder and non-responder patient samples and identified midkine (MDK), a multifunctional cytokine, as a potent repressor of IFN signaling in both tumor and immune cells. MDK expression dampened MHC-I presentation in human tumor cells and reduced activation of antigen-presenting cells, disrupting tumor immunity at multiple levels. In contrast to prior studies, we identified MDK as specifically enriched in neuroendocrine cancers such as MCC and small cell lung cancer compared with melanoma, suggesting the importance of lineage- and context-specific targeting. Our results demonstrate the utility of high-dimensional controlled perturbation of patient samples to identify mechanisms of innate immune response and resistance and demonstrate an actionable path towards clinical development of MDK-inhibiting therapies including FDA-approved ALK inhibitors in neuroendocrine cancers.

cancer biology↗

bioRxiv2025

Visual Attention in Peripersonal Space

Bringing the hand near a visual stimulus enhances visual processing. This effect is linked to peripersonal space (PPS), the body-centered region where visual and proprioceptive information interact. Despite extensive behavioral evidence, the neural basis of this interaction in early visual cortex remains unclear. In this study, we investigated how hand proximity modulates orientation selectivity in area V2 by recording single-neuron responses from two rhesus monkeys. The monkeys performed a fixation task while their hand was positioned near a visual stimulus while either being visible or occluded, and compared with when the hand was away from the stimulus. When the near hand was visible, neural firing rates in V2 were significantly higher, accompanied by sharper orientation tuning. In contrast, occluding the hand broadened orientation tuning compared to when the hand was away. These effects emerged rapidly after stimulus onset and were coherent across the population, demonstrating that PPS is actively prioritized during visual processing. Together, the findings reveal two complementary (feedback) signals in V2: a congruence-driven enhancement when visual and proprioceptive inputs align, and a mismatch-driven suppression when they conflict, indicating that V2 integrates multisensory cues to encode PPS and support action-relevant visual processing.

neuroscience↗

bioRxiv2023

FGF-21 Conducts a Liver-Brain-Kidney Axis to Promote Renal Cell Carcinoma

Metabolic homeostasis is one of the most exquisitely tuned systems in mammalian physiology. Metabolic homeostasis requires multiple redundant systems to cooperate to maintain blood glucose concentrations in a narrow range, despite a multitude of physiological and pathophysiological pressures. Cancer is one of the canonical pathophysiological settings in which metabolism plays a key role. In this study, we utilized REnal Gluconeogenesis Analytical Leads (REGAL), a liquid chromatography-mass spectrometry/mass spectrometry-based stable isotope tracer method that we developed to show that in conditions of metabolic stress, the fasting hepatokine fibroblast growth factor-21 (FGF-21)1, 2 coordinates a liver-brain-kidney axis to promote renal gluconeogenesis. FGF-21 promotes renal gluconeogenesis by enhancing {beta}2 adrenergic receptor (Adrb2)-driven, adipose triglyceride lipase (ATGL)-mediated intrarenal lipolysis. Further, we show that this liver-brain-kidney axis promotes gluconeogenesis in the renal parenchyma in mice and humans with renal cell carcinoma (RCC). This increased gluconeogenesis is, in turn, associated with accelerated RCC progression. We identify Adrb2 blockade as a new class of therapy for RCC in mice, with confirmatory data in human patients. In summary, these data reveal a new metabolic function of FGF-21 in driving renal gluconeogenesis, and demonstrate that inhibition of renal gluconeogenesis by FGF-21 antagonism deserves attention as a new therapeutic approach to RCC.

physiology↗

bioRxiv2022

Degraded RNA from human anterior cruciate ligaments yields valid gene expression profiles

BackgroundCorrelating gene expression patterns with biomechanical properties of connective tissues provides insight into molecular processes underlying development and maintenance of the tissues physical characteristics. Cadaveric tissues such as human knees are widely considered suitable for biomechanical studies, but their usefulness for gene expression experiments is potentially limited by unavoidable, nuclease-mediated degradation of RNA. MethodsWe quantified mRNAs encoding 84 extracellular matrix components and five housekeeping proteins in intact and partially degraded RNA from human anterior cruciate ligaments (ACLs), and compared relative amounts of the individual mRNAs by regression analysis. ResultsHuman ACL RNA degraded in vitro by limited ribonuclease digestion (N=6) resembled degraded RNA isolated from cadaveric tissue. PCR threshold cycle (Ct) values from degraded RNAs ranged variably higher than values obtained from their corresponding non-degraded RNAs, reflecting both the expected loss of target templates in the degraded preparations as well as differences in the extent of degradation. Relative Ct values obtained for mRNA targets in degraded preparations correlated strongly with the corresponding target levels in non-degraded RNA, both for each ACL as well as for pooled results from all six ACLs. Nuclease-mediated degradation produced similar, strongly correlated losses of housekeeping and non-housekeeping gene mRNAs. Expression profiling of RNA degraded in situ yielded comparable results, confirming that in vitro digestion suitably mimicked degradation by endogenous ribonucleases in frozen and thawed ACL. ConclusionPCR-based expression analyses can yield valid mRNA profiles from partially degraded RNA preparations such as those obtained from cadaveric knees and other skeletal motion segments used in biomechanical studies. Legitimate comparisons between variably degraded tissues can be made by normalizing quantitative data to an appropriate housekeeping transcript.

molecular biology↗

bioRxiv2020

Adolescent rats show estrous cycle-mediated sex differences in extinction of conditioned fear

Anxiety disorders are more prevalent in females than males, and frequently emerge during adolescence. Despite this, preclinical research commonly focuses on adult males. Here we use Pavlovian fear conditioning and extinction in adolescent male and female rats to understand sex- and age-dependent processes relevant to anxiety disorders. In experiment 1, 35-day-old male and female rats were exposed to 6 pairings of a conditioned stimulus (CS, a tone) with an aversive unconditioned stimulus (US, a footshock). The next day they were extinguished in a contextually distinct chamber, via 60 presentations of the CS without the US. Extinction recall was tested 24 hours later in the extinction context. Estrous phase was monitored by cytology on vaginal smears taken 1 hour after each behavioral session. In experiment 2, male and female rats were given sham surgery or gonadectomy at 21 days of age. They were then trained and tested as for experiment 1. We observed that females in proestrus or met/diestrus during extinction showed delayed extinction and impaired extinction recall the next day compared to males. Ovariectomy enhanced extinction for female rats, but orchidectomy delayed extinction for males. Plasma analyses showed that met/di/proestrus phases were associated with high estradiol levels. These findings suggest that high plasma estradiol levels impair extinction for adolescent females. While these results contradict what is observed in adult animals, they are consistent with the prevalence of anxiety disorders observed in females. Our findings have important implications for understanding and treating anxiety in adolescents, particularly where treatment involves extinction-based therapies.

animal behavior and cognition↗

bioRxiv2019

Honeybees adjust colour preferences in response to concurrent social information from conspecifics and heterospecifics

Bees efficiently learn asocial and social cues to optimise foraging from fluctuating floral resources. However, it remains unclear how bees respond to divergent sources of social information, and whether such social cues might modify bees’ natural preferences for non-social cues (e.g. flower colour), hence affecting foraging decisions. Here, we investigated honeybees’ (Apis mellifera) inspection and choices of unfamiliar flowers based on both natural colour preferences and simultaneous foraging information from conspecifics and heterospecifics. Individual honeybees’ preferences for flowers were recorded when the reward levels of a learned flower type had declined and novel-coloured flowers were available where they would find either no social information or one conspecific and one heterospecific (Bombus terrestris), each foraging from a different coloured flower (magenta or yellow). Honeybees showed a natural preference for magenta flowers. Honeybees modified their inspection of both types of flowers in response to conspecific and heterospecific social information. The presence of either demonstrator on the less-preferred yellow flower increased honeybees’ inspection of yellow flowers. Conspecific social information influenced observers’ foraging choices of yellow flowers, thus outweighing their original preference for magenta flowers. This effect was not elicited by heterospecific social information. Our results indicate that flower colour preferences of honeybees are rapidly adjusted in response to conspecific social information, which in turn is preferred over heterospecific information, possibly favouring the transmission of adaptive foraging information within species.Competing Interest StatementThe authors have declared no competing interest.View Full Text

animal behavior and cognition↗

bioRxiv2018

Temporal correlation of elevated PRMT1 gene expression with mushroom body neurogenesis during bumblebee brain development

Proper neural development in insects depends on the controlled proliferation and differentiation of neural precursors. In holometabolous insects, these processes must be coordinated during larval and pupal development. Recently, protein arginine methylation has come into focus as an important mechanism of controlling neural stem cell proliferation and differentiation in mammals. Whether a similar mechanism is at work in insects is unknown. We investigated this possibility by determining the expression pattern of three protein arginine methyltransferase mRNAs (PRMT1, 4 and 5) in the developing brain of bumblebees by in situ hybridisation. We detected expression in neural precursors and neurons in functionally important brain areas throughout development. We found markedly higher expression of PRMT1, but not PRMT4 and PRMT5, in regions of mushroom bodies containing dividing cells during pupal stages at the time of active neurogenesis within this brain area. At later stages of development, PRMT1 expression levels were found to be uniform and did not correlate with actively dividing cells. Our study suggests a role for PRMT1 in regulating neural precursor divisions in the mushroom bodies of bumblebees during the period of neurogenesis.

developmental biology↗