Biology subjects

Dunning, J. L.

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

5 recordsLinked to original sources

bioRxiv2026

Functional remodeling of the parasubthalamic nucleus drives alcohol drinking escalation in dependence

The neurocircuitry changes mediating the development and maintenance of an alcohol use disorder are complex and dynamic. The parasubthalamic nucleus (PSTN), a small nucleus of the posterior lateral hypothalamus best known for suppressing appetite, is interconnected with brain regions disrupted in addiction; yet its potential role in the regulation of alcohol consumption had never been examined. Here we show that the PSTN exerts potent control over alcohol drinking in mice. Remarkably, the influence of endogenous PSTN activity on voluntary alcohol consumption switches from inhibitory to stimulatory upon induction of alcohol dependence. Among PSTN cells, Crh neurons represent a unique subpopulation that promotes alcohol drinking and fires more in dependent mice. Alcohol intake escalation driven by PSTN Crh neurons involves thalamic output and behavioral disinhibition. Based on our results, PSTN Crh neurons could represent a critical node in the brain circuitry overactive in alcohol addiction driven by reward seeking in humans.

neuroscience↗

bioRxiv2026

Arrestin-3 promotes locomotor sensitization to psychostimulants via JNK signaling in nucleus accumbens

Arrestins play key role in desensitization of G protein-coupled receptors. Direct signaling role of arrestins has also been documented. Two ubiquitously expressed arrestin isoforms, arrestin-2 and -3 (Arr3), perform similarly in receptor desensitization and share many signaling functions, enabling them to substitute for one another. However, certain signaling roles are specific to each isoform. Mice lacking Arr3 (A3KO) show blunted acute responsiveness to the locomotor stimulatory effect of amphetamine (AMPH). Here we demonstrate that AMPH- and cocaine-induced locomotion of A3KO mice is significantly reduced. This loss-of-function phenotype suggests that Arr3-mediated signaling contributes to the effect. Virus-driven expression of Arr3 in caudate-putamen of A3KO and wild type mice suppressed AMPH-induced locomotion. In contrast, restoration of Arr3 in nucleus accumbens rescued locomotor response. Thus, in caudate-putamen Arr3 participates in the desensitization of dopamine receptors, whereas Arr3-dependent signaling in nucleus accumbens underlies the molecular mechanism of the locomotor response and sensitization. Using monofunctional Arr3-derived peptides, we showed that in the nucleus accumbens Arr3 promoted drug-induced locomotor responses via facilitation of JNK3 activation.

neuroscience↗

bioRxiv2024

Mouse parasubthalamic Crh neurons drive alcohol drinking escalation and behavioral disinhibition

Corticotropin-releasing factor (CRF, encoded by Crh) signaling is thought to play a critical role in the development of excessive alcohol drinking and the emotional and physical pain associated with alcohol withdrawal. Here, we investigated the parasubthalamic nucleus (PSTN) as a potential source of CRF relevant to the control of alcohol consumption, affect, and nociception in mice. We identified PSTN Crh neurons as a neuronal subpopulation that exerts a potent and unique influence on behavior by promoting not only alcohol but also saccharin drinking, while PSTN neurons are otherwise known to suppress consummatory behaviors. Furthermore, PSTN Crh neurons are causally implicated in the escalation of alcohol and saccharin intake produced by chronic intermittent ethanol (CIE) vapor inhalation, a mouse model of alcohol use disorder. In contrast to our predictions, the ability of PSTN Crh neurons to increase alcohol drinking is not mediated by CRF1 signaling. Moreover, the pattern of behavioral disinhibition and reduced nociception driven by their activation does not support a role of negative reinforcement as a motivational basis for the concomitant increase in alcohol drinking. Finally, silencing Crh expression in the PSTN slowed down the escalation of alcohol intake in mice exposed to CIE and accelerated their recovery from withdrawal-induced mechanical hyperalgesia. Altogether, our results suggest that PSTN Crh neurons may represent an important node in the brain circuitry linking alcohol use disorder with sweet liking and novelty seeking.

neuroscience↗

bioRxiv2023

Arrestin-3-assisted activation of JNK3 mediates dopaminergic behavioral and signaling plasticity in vivo.

In rodents with unilateral ablation of the substantia nigra neurons supplying dopamine to the striatum, chronic treatment with the dopamine precursor L-DOPA or dopamine agonists induces a progressive increase of behavioral responses, a process known as behavioral sensitization. The sensitization is blunted in arrestin-3 knockout mice. Using virus-mediated gene delivery to the dopamine-depleted striatum of arrestin-3 knockout mice, we found that the restoration of arrestin-3 fully rescued behavioral sensitization, whereas its mutant defective in JNK activation did not. A 25-residue arrestin-3-derived peptide that facilitates JNK3 activation in cells, expressed ubiquitously or selectively in the direct pathway striatal neurons, fully rescued sensitization, whereas an inactive homologous arrestin-2-derived peptide did not. Behavioral rescue was accompanied by the restoration of JNK3 activity and of JNK-dependent phosphorylation of the transcription factor c-Jun in the dopamine-depleted striatum. Thus, arrestin-3-dependent JNK3 activation in direct pathway neurons is a critical element of the molecular mechanism underlying sensitization.

neuroscience↗

bioRxiv2023

The parasubthalamic nucleus refeeding ensemble delays feeding initiation

The parasubthalamic nucleus (PSTN) is responsive to refeeding after food deprivation and PSTN subpopulations can suppress feeding. However, no study directly addressed the role of PSTN neurons activated upon food access resumption. Here we show that the ensemble of refeeding-activated PSTN neurons drastically increases the latency to initiate refeeding with both familiar and novel food but exerts limited control over the amount of food consumed by hungry mice. This ensemble also delays sucrose consumption but accelerates water consumption in thirsty mice. We next sought to identify which subpopulations of PSTN neurons might be driving these effects. We discovered that PSTN Tac1 neurons projecting to the CeA selectively suppress feeding initiation while PSTN Crh neurons surprisingly promote the consumption of novel, palatable substances. Our results demonstrate the key role of endogenous PSTN activity in the control of feeding initiation and identify PSTN subpopulations counteracting each others influence on consummatory behaviors.

neuroscience↗