Biology subjects

Dani, J. A.

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

6 recordsLinked to original sources

bioRxiv2026

Chronic Alcohol Exposure Alters Expression of GluN3A-NMDA Receptors in Adult VTA DA Neurons

N-methyl-D-aspartate receptor (NMDAR) neurotransmission plays a central role in the neurophysiological and behavioral adaptations produced by chronic alcohol (EtOH) exposure and withdrawal. Although alcohol-induced changes in canonical NMDAR subtypes have been extensively studied, the mechanisms by which prolonged alcohol exposure remodels NMDAR function remain incompletely understood. To investigate the impact of chronic voluntary alcohol consumption on glutamatergic signaling, adult C57BL/6J mice were exposed to 20% EtOH using the intermittent two-bottle choice (I2BC) approach for 8 weeks and NMDAR function was examined in ventral tegmental area (VTA) dopamine (DA) neurons using whole-cell electrophysiology. Chronic EtOH exposure reduced NMDA-evoked currents, an effect that became more pronounced during withdrawal. Withdrawal also reduced NMDAR outward current rectification, indicating that chronic alcohol exposure altered the biophysical properties of NMDAR-mediated signaling. These unexpected observations led us to investigate the contribution of GluN3A-containing NMDARs. Pharmacological analyses revealed a significant increase in the proportion of VTA DA neurons expressing functional GluN3A-containing receptors following chronic EtOH exposure, with all tested neurons expressing these receptors during withdrawal. Glycine activation directly depolarized VTA DA neurons and increased action potential firing, demonstrating that the recruited receptors function as excitatory NMDARs. Moreover, the alcohol-induced changes in NMDAR currents, receptor pharmacology, and glycine responsiveness were absent in GluN3A null mice. Together, these findings identify functional recruitment of GluN3A-containing NMDARs as a previously unrecognized neuroadaptation through which chronic alcohol remodels glutamatergic signaling in the adult VTA.

neuroscience↗

bioRxiv2025

Ventral Tegmental Area Glutamatergic Neurons Suppress Hippocampal Sharp-wave Ripples and Induce Head Movements in Mice

Sharp-wave ripples are brief, high-frequency hippocampal oscillations crucial for memory consolidation, occurring predominantly during the non-rapid-eye-movement (NREM) sleep. While ripples are generated intrinsically within the hippocampus, growing evidence suggests that their occurrence is modulated by subcortical regions. Whether the ventral tegmental area (VTA)--a subcortical region that directly projects to the hippocampus--regulates ripple activity remains unknown. To investigate this, we optogenetically activated VTA neurons during NREM sleep and recorded ripple activity in the dorsal hippocampus via field recording electrodes. Using cell-type specific excitatory opsin expression in the VTA, we found that activation of glutamatergic (vGlut2+) neurons strongly suppressed ripple incidence. In contrast, activation of GABAergic (vGAT+) neurons produced weak suppression, and activation of dopaminergic (DAT+) neurons showed no effect. During ripple suppression by glutamatergic activation, we observed small but consistent head movements. Trial-by-trial analysis revealed no correlation between head movement and ripple suppression. Furthermore, glutamatergic activation during wakefulness also led to head movement, suggesting that ripple suppression and head movement could be dissociated. Overall, our results suggest that VTA vGlut2+ neurons play a role in head movement and that their activation suppresses hippocampal sharp-wave ripples during NREM sleep, offering a potential way to alter memory consolidation.

neuroscience↗

bioRxiv2025

Paradoxical ventral tegmental area GABA signaling drives enhanced morphine reward after adolescent nicotine

BackgroundAn important yet poorly understood risk factor for opioid use disorder is adolescent nicotine use. We investigated the neural mechanisms underlying this understudied interaction. MethodsMale and female adolescent mice received two-weeks of nicotine water (Adol Nic) or plain water (Adol Water). In adulthood, mice underwent three morphine tests: conditioned place preference (CPP), locomotor sensitization, and two-bottle choice. Ex vivo ventral tegmental area (VTA) brain slices were assessed via patch clamp for GABA and dopamine (DA) neuron morphine responses. Finally, VTA GABA neurons were chemogenetically inhibited during morphine CPP. ResultsIn adulthood, Adol Nic mice had greater morphine CPP, more morphine locomotor sensitization, and more choice-based oral morphine consumption vs. Adol Water mice. In contrast, adult mice given nicotine vs. water had similar morphine CPP. Patch clamp analysis of VTA neurons from adult Adol Water mice showed canonical cell-type responses to bath-applied morphine: fewer action potentials in GABA neurons and more in DA neurons. Paradoxically, VTA GABA and DA neurons from adult Adol Nic mice did not show these morphine responses. In support of a causal relationship between GABA neuron firing and reward behavior, chemogenetic inhibition of VTA GABA neurons in Adol Water mice during pairing increased morphine CPP. In contrast, inhibition of VTA GABA neurons in Adol Nic mice brought morphine CPP down to control levels. ConclusionsThese data reveal an electrophysiological mechanism by which adolescent nicotine intake promotes morphine reward later in life, showing that adolescent nicotine exposure alters reward circuitry well into adulthood.

neuroscience↗

bioRxiv2024

ACSS2 upregulation enhances neuronal resilience to aging and tau-associated neurodegeneration

Epigenetic mechanisms, including histone acetylation, are pivotal for learning and memory, with a role in neuronal function in Alzheimers disease and Related Dementia (ADRD). Acetyl-CoA synthetase 2 (ACSS2), an enzyme that generates acetyl-CoA, is central to histone acetylation and gene regulation, particularly in neurons, due to their unique metabolic demands and postmitotic state. ACSS2 can be recruited to the nucleus and chromatin, locally supplying acetyl-CoA to directly fuel histone acetyltransferase enzymes and key neuronal gene expression. This regulatory mechanism may be a promising target for therapeutic intervention in neurodegenerative diseases. Previously we showed that systemic ACSS2 deletion in mice, although largely normal in physiology, is greatly impaired in memory. Here we investigated whether increasing ACSS2 levels could protect neurons against disease and age-associated cognitive decline. Given the role of tau in ADRD, we used primary hippocampal neurons that mimic the sporadic development of tau pathology and the P301S transgenic mouse model for tau-induced memory decline. Our results show that ACSS2 upregulation mitigates tau-induced transcriptional alterations, enhances neuronal resilience against tau pathology, improves long-term potentiation, and ameliorates memory deficits. Expanding upon these findings, we reveal that increasing histone acetylation through ACSS2 upregulation improves age-associated memory decline. These findings indicate that increasing ACSS2 is highly effective in countering age- and tau-induced transcriptome changes, preserving elevated levels of synaptic genes, and safeguarding synaptic integrity. We thus highlight ACSS2 as a key player in the epigenetic regulation of cognitive aging and ADRD, providing a foundation for targeted therapeutics to enhance brain resilience and function. SummaryACSS2 upregulation protects neurons from disease and age-related decline by enhancing synaptic and longevity gene expression.

neuroscience↗

bioRxiv2020

Fear Conditioning Potentiates the Hippocampal CA1 Commissural Pathway In vivo and Increases Awake Phase Sleep

The hippocampus is essential for spatial learning and memory. To assess learning we used contextual fear conditioning (cFC), where animals learn to associate a place with aversive events like foot-shocks. Candidate memory mechanisms for cFC are long-term potentiation and long-term depression, but there is little direct evidence of them operating in the hippocampus in vivo following cFC. Also, little is known about the behavioral state changes induced by cFC. To address these issues, we recorded local field potentials in freely behaving mice by stimulating in the left dorsal CA1 region and recording in the right dorsal CA1 region. Synaptic strength in the commissural pathway was monitored by measuring field excitatory postsynaptic potentials (fEPSPs) before and after cFC. After cFC, the commissural pathways synaptic strength was potentiated. Although recordings occurred during the wake phase of the light/dark cycle, the mice slept more in the post-conditioning period than in the pre-conditioning period. Relative to awake periods, in non-rapid eye movement (NREM) sleep the fEPSPs were larger in both pre- and post-conditioning periods. We also found a significant negative correlation between the animals speed and fEPSP size. Therefore, to avoid confounds in the fEFSP potentiation estimates, we controlled for speed-related and sleep-related fEPSP changes and still found that cFC induced long-term potentiation, but no significant long-term depression. Synaptic strength changes were not found in the control group that simply explored the fear-conditioning chamber, indicating that exploration of the novel place did not produce the measurable effects caused by cFC. These results show that following cFC, the CA1 commissural pathway is potentiated, likely contributing to the functional integration of the left and right hippocampi in fear memory consolidation. In addition, the cFC paradigm produces significant changes in an animals behavioral state, which are observable as proximal changes in sleep patterns.

neuroscience↗

bioRxiv2019

Adolescent Stress Increases Adult Ethanol Self-administration and Alters Ventral Tegmental Area GABA Signaling

Alcohol use disorders (AUDs) continue to be a significant public health problem. Early life stress and adversity have long-lasting effects on a wide range of behaviors, including responses to drugs of abuse. Epidemiological evidence indicates that exposure to early life stress contributes to alcohol use disorders and, while it is known that stress and alcohol both act on overlapping mesolimbic circuitry, the cellular mechanisms underlying the relationship between stress and alcohol intake are not well understood. Previous work has demonstrated that acute stress increases ethanol intake mediated by changes in GABA signaling within the ventral tegmental area (VTA). Here we investigated if adolescent stress exposure might elicit long-term, persistent increases in ethanol self-administration associated with altered VTA GABA signaling. To this end, we exposed adolescent postnatal day (PND) 28 male rats to 14 days of chronic variable stress (CVS) and then examined operant ethanol self-administration begun at least 30 days later. We found that adolescent stress exposure resulted in significantly increased ethanol self-administration in adulthood. In contrast, adult (PND 82) male rats exposed to the same CVS protocol did not display increased ethanol self-administration that was begun 30 days later. Furthermore, we found that adolescent stress exposure resulted in enhancement of ethanol-induced GABA signaling onto VTA dopamine neurons and impairments in VTA GABA chloride homeostasis. The results indicate that adolescence is a period vulnerable to stress, which produces long-term changes in VTA GABA signaling associated with increased ethanol self-administration behavior.

neuroscience↗