Biology subjects

Wojick, J. A.

Publications and source records attributed to Wojick, J. A..

7 recordsLinked to original sources

bioRxiv2026

The role of serotonin in the orbitofrontal cortex in alcohol consumption

Binge alcohol drinking is a public health concern that can dramatically increase the risk for development of alcohol use disorder (AUD). Continued alcohol drinking in the face of negative consequences is another key feature of AUD. A better understanding of the neural circuitry that regulates these behaviors could provide insight as to novel treatments for AUD. Serotonin is a neurotransmitter that has been implicated in alcohol consumption in both human studies and animal models. The orbitofrontal cortex (OFC) is a brain region that both receives serotonergic input from the dorsal raphe and has been implicated in AUD. However, how volitional alcohol consumption impacts serotonin signaling within the OFC and how this contributes to alcohol related behaviors is unknown. Here, we show that a history of alcohol consumption alters the ability of 5-HT to hyperpolarize OFC pyramidal neurons in mice and monkeys. Consistent with this, a history of binge alcohol consumption decreases the expression of the 5-HT1A but not 5-HT2A receptor in the OFC from mice. Next, we show that deletion of the 5-HT1A receptor from the OFC increased alcohol intake and preference in male, but not female mice. Finally, we found that 5-HT1A receptor deletion led to increased quinine-adulterated alcohol intake, a measure of aversion-resistant drinking, in both male and female mice. Altogether, we identified serotonin signaling in the OFC as key target for modulation of binge and compulsive alcohol consumption.

neuroscience↗

bioRxiv2025

Adolescent alcohol exposure disrupts extinction learning and retrosplenial cortex physiology in adult males

Adolescent binge drinking can lead to a myriad of issues in adulthood, including psychiatric comorbidities that worsen clinical prognosis. Efforts to understand the effects of adolescent alcohol exposure on later health outcomes have unveiled lasting effects on physiology of brain regions critical for associative learning processes, including the hippocampus and prefrontal cortex (PFC). Here, we tested the hypothesis that adolescent alcohol exposure would produce lasting alterations in physiology within the retrosplenial cortex (RSC), another region critical for associative learning that is reciprocally connected to the hippocampus and PFC. In support of this hypothesis, we found that adolescent intermittent ethanol (AIE) vapor exposure resulted in lasting reductions in intrinsic excitability in RSC pyramidal cells of adult mice. Importantly, these changes were sex-specific, occurring in males but not females. This work suggests that the RSC may be a key, vulnerable locus to the detrimental effects of adolescent alcohol.

neuroscience↗

bioRxiv2025

Lateral hypothalamus CRFR1 regulation of chronic binge drinking: divergence along anterior-posterior axis

Binge alcohol drinking increases the risk of developing an alcohol use disorder (AUD) and comorbid psychopathology. The lateral hypothalamus (LH) is a brain structure that integrates cognitive and sensory information to tightly regulate motivated behavior, including binge drinking. Importantly, LH function is vulnerable to modulation by the pro-stress neuropeptide corticotropin-releasing factor (CRF), and acute antagonism of CRF receptor 1 (CRFR1) in the LH blunts binge drinking. However, the role of LH CRFR1 in chronic binge drinking is unknown. We used genetically targeted knockdown (KD) of CRFR1 in the LH of male and female mice followed by three weeks of binge drinking using the "Drinking in the Dark" (DID) model. CRFR1 KD in the posterior LH increased alcohol consumption, independent of sex, with no effect of KD in the anterior LH. Consistent with this, total alcohol consumption was negatively correlated with the location of CRFR1 KD in the LH along the anterior-posterior axis. CRFR1 KD did not alter water consumption or body weight, suggesting the effects of CRFR1 KD on alcohol consumption were not due to broad disruption of fluid intake or homeostatic function. In contrast to the observed effects on binge drinking, CRFR1 KD increased anxiety-like behavior and blunted sucrose preference, independent of KD location in the LH. Our findings provide foundational insight into LH function in the context of AUD and prompt further investigation into the divergent roles that distinct circuitry or cell populations along the anterior-posterior axis of the LH may play in binge drinking. HighlightsO_LICRFR1 knockdown in posterior LH increased alcohol drinking independent of sex C_LIO_LIAlcohol intake negatively correlated with AP location of CRFR1 knockdown in LH C_LIO_LICRFR1 knockdown was anxiogenic with more pronounced effects in females C_LIO_LISucrose preference was blunted by CRFR1 knockdown C_LI

neuroscience↗

bioRxiv2025

Convergent state-control of endogenous opioid analgesia

Pain is a dynamic and nonlinear experience shaped by injury and contextual factors, including expectations of future pain or relief1. While {micro} opioid receptors are central to the analgesic effects of opioid drugs, the endogenous opioid neurocircuitry underlying pain and placebo analgesia remains poorly understood. The ventrolateral column of the posterior periaqueductal gray is a critical hub for nociception and endogenous analgesia mediated by opioid signaling2. However, significant gaps remain in understanding the cell-type identities, the sub-second neural dynamics involved in pain modulation, the role of endogenous peptide neuromodulators, and the contextual factors influencing these processes. Using spatial mapping with single-nuclei RNA sequencing of pain-active neurons projecting to distinct long-range brain targets, alongside cell type-specific and activity-dependent genetic tools for in vivo optical recordings and modulation of neural activity and opioid peptide release, we identified a functional dichotomy in the ventrolateral periaqueductal gray. Neurons expressing {micro} opioid receptors encode active nociceptive states, whereas enkephalin-releasing neurons drive pain relief during recovery from injury, in response to learned fear predictions, and during placebo analgesia. Finally, by leveraging the functional effects of placebo analgesia, we used direct optogenetic activation of vlPAG enkephalin neurons to drive opioid peptide release, resulting in a robust reduction in pain. These findings show that diverse need states converge on a shared midbrain circuit that releases endogenous opioids with high spatiotemporal precision to suppress nociceptive activity and promote analgesia.

neuroscience↗

bioRxiv2024

Mimicking opioid analgesia in cortical pain circuits

The anterior cingulate cortex is a key brain region involved in the affective and motivational dimensions of pain, yet how opioid analgesics modulate this cortical circuit remains unclear. Uncovering how opioids alter nociceptive neural dynamics to produce pain relief is essential for developing safer and more targeted treatments for chronic pain. Here we show that a population of cingulate neurons encodes spontaneous pain-related behaviors and is selectively modulated by morphine. Using deep-learning behavioral analyses combined with longitudinal neural recordings in mice, we identified a persistent shift in cortical activity patterns following nerve injury that reflects the emergence of an unpleasant, affective chronic pain state. Morphine reversed these neuropathic neural dynamics and reduced affective-motivational behaviors without altering sensory detection or reflexive responses, mirroring how opioids alleviate pain unpleasantness in humans. Leveraging these findings, we built a biologically inspired gene therapy that targets opioid-sensitive neurons in the cingulate using a synthetic mu-opioid receptor promoter to drive chemogenetic inhibition. This opioid-mimetic gene therapy recapitulated the analgesic effects of morphine during chronic neuropathic pain, thereby offering a new strategy for precision pain management targeting a key nociceptive cortical opioid circuit with safe, on-demand analgesia. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=40 SRC="FIGDIR/small/591113v2_ufig1.gif" ALT="Figure 1"> View larger version (28K): org.highwire.dtl.DTLVardef@d294c0org.highwire.dtl.DTLVardef@123d4f4org.highwire.dtl.DTLVardef@1720deborg.highwire.dtl.DTLVardef@efc632_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2024

A nociceptive amygdala-striatal pathway for chronic pain aversion

The basolateral amygdala (BLA) is essential for assigning positive or negative valence to sensory stimuli. Noxious stimuli that cause pain are encoded by an ensemble of nociceptive BLA projection neurons (BLAnoci ensemble). However, the role of the BLAnoci ensemble in mediating behavior changes and the molecular signatures and downstream targets distinguishing this ensemble remain poorly understood. Here, we show that the same BLAnoci ensemble neurons are required for both acute and chronic neuropathic pain behavior. Using single nucleus RNA-sequencing, we characterized the effect of acute and chronic pain on the BLA and identified enrichment for genes with known functions in axonal and synaptic organization and pain perception. We thus examined the brain-wide targets of the BLAnoci ensemble and uncovered a previously undescribed nociceptive hotspot of the nucleus accumbens shell (NAcSh) that mirrors the stability and specificity of the BLAnoci ensemble and is recruited in chronic pain. Notably, BLAnoci ensemble axons transmit acute and neuropathic nociceptive information to the NAcSh, highlighting this nociceptive amygdala-striatal circuit as a unique pathway for affective-motivational responses across pain states.

neuroscience↗

bioRxiv2020

A machine-vision approach for automated pain measurement at millisecond timescales

Objective and automatic measurement of pain in mice remains a barrier for discovery in both basic and translational neuroscience. Here we capture rapid paw kinematics during pain behavior in mice with high-speed videography and automated paw tracking with machine and deep learning approaches. Our statistical software platform, PAWS (Pain Assessment at Withdrawal Speeds), uses a univariate projection of paw position over time to automatically quantify fast paw dynamics at the onset of paw withdrawal and also lingering pain-related behaviors such as paw guarding and shaking. Applied to innocuous and noxious stimuli across six inbred mouse strains, a linear discriminant analysis reveals a two-dimensional subspace that separates painful from non-painful stimuli on one axis, and further distinguishes the severity of pain on the second axis. Automated paw tracking combined with PAWS reveals behaviorally-divergent mouse strains that display hypo- and hyper-sensitivity to mechanical stimuli. To demonstrate the efficacy of PAWS for detecting hypersensitivity to noxious stimuli, we chemogenetically activated pain-aversion neurons in the amygdala, which further separated the behavioral representation of pain-related behaviors along a low-dimensional path. Taken together, this automated pain quantification approach should increase the ease and objectivity of collecting rigorous behavioral data, and it is compatible with other neural circuit dissection tools for determining the mouse pain state.

neuroscience↗