Ventral Tegmental Area Research Articles

Hypocretin modulation of behavioral coping strategies for social stress.

Best known for promoting wakefulness and arousal, the neuropeptide hypocretin (Hcrt) also plays an important role in mediating stress responses, including social stress. However, central and systemic manipulation of the Hcrt system has produced diverse behavioral outcomes in animal models. In this review, we first focus on studies where similar manipulations of the Hcrt system led to divergent coping behaviors. We hypothesize that Hcrt differentially facilitates active and passive coping behaviors in response to social stress by acting in different brain regions and on different cell types. We then focus on region and cell type-specific effects of Hcrt in the ventral pallidum, lateral habenula, ventral tegmental area, nucleus accumbens, amygdala, and bed nucleus of the stria terminalis. Overall, the evidence suggests that rather than enhancing or inhibiting behavioral responses to social stress, Hcrt may signal the heightened arousal associated with stressful contexts. The resulting behavioral effects depend on which circuits Hcrt release occurs in and which receptor types are activated. Further study is needed to determine how and why circuit specific activation of Hcrt neurons occurs.

Possible Mechanisms of the Influence of Oxytocin and Vazopressin on Perception and Memory of Odors and on Social Behavior

A possible mechanism is proposed for the influence of oxytocin and vasopressin on the functioning of the neural network in the CNS, in which olfactory information is processed and stored, and which plays an important role in social behavior. The effect of these neuropeptides on postsynaptic receptors associated with Gq/11 proteins contributes to the induction of LTP of the efficacy of excitatory synaptic inputs to the main projection cells and to inhibitory interneurons in the prefrontal cortex, hippocampus, piriform cortex, anterior olfactory nucleus, olfactory bulb and nucleus accumbens, including the olfactory tubercle. As a result of disynaptic inhibition in each of the structures, the signal-to-noise ratio is improved and the transmission of strong signals through projection neurons to their target cells is facilitated. Due to the fact, that oxytocin promotes the release of dopamine by the neurons of the ventral tegmental area, the conditions for processing and memorizing olfactory information in the interconnected olfactory and hippocampal neural networks, including cortical and subcortical structures, are improved, and attention is also included in this processing. Long-term modification of the effectiveness of interneuronal connections in these networks under the influence of oxytocin and dopamine contributes to the formation and stabilization of contrasting neuronal representation of odors formed in cortical areas. Orientation of attention increases the significance of socially important olfactory stimuli and improves the conditions for the functioning of the reinforcement system necessary for adequate social behavior. Taking into account the known data on the correlation between social behavior and the density of oxytocin and vasopressin receptors on neurons of different structures, understanding the mechanisms of the influence of these neuropeptides on the functioning of the olfactory system can be useful for finding ways to correct behavior if necessary.

Joint anatomical, histological and imaging investigation of the midbrain target region for superolateral medial forebrain bundle (slMFB) DBS.

Deep Brain Stimulation (DBS) of the superolateral branch of the medial forebrain bundle (slMFB) is currently being researched in clinical trials and open case series as a therapeutic option for treatment resistant major depressive disorder (TR-MDD) and treatment resistant obsessive-compulsive disorder (TR-OCD). There are numerous publications describing stimulation in such proximity to the ventral tegmental area (VTA) and open questions remain concerning the stimulation target and its functional environment. As of right now, we are not aware of any publications that compare the typical electrode placements with the histologically supported tractographic depiction of the target structure. We used three cadaver midbrain samples with presumed unaltered anatomy. After fixation, staining and slicing, the histological samples were warped to the MNI (Montreal Neurological Institute) big brain environment. Utilizing a tractographic atlas, a qualitative analysis of the typical slMFB stimulation site in the lateral VTA utilizing a subset of clinically implanted DBS electrodes in n=12 patients, successfully implanted for TR-OCD was performed. A joint qualitative overlay analysis of predominantly tyrosine-hydroxylase stained histology at different resolutions in an anatomical common space was achieved. Localization of the DBS-lead bodies was found in the typical positions in front of the red nuclei in the lateral VTA. DBS lead tip region positions explained the oculomotor side effects of stimulation related to para-nigral or parabrachial pigmented sub-nuclei of the VTA, respectively. The location of active electrode contacts suggest downstream and antidromic effects on the greater VTA related medial forebrain bundle system. This is the first dedicated joint histopathological overlay analysis of DBS electrodes targeting the slMFB and lateral VTA in a common anatomical space. This analysis might serve to better understand the DBS target region for this procedure.

Social isolation induces addictive behavior and increases release of dopamine in the <i>nucleus accumbens</i> in response to stimulation of the positive reinforcing zone

The study of the role of social isolation in the pathogenesis of addictive behavior disorders is an important medical and biological problem. Of particular importance are the limitations of social experience in ontogenesis. This work makes an attempt to find a connection between social isolation in ontogenesis and impulsive-compulsive behavior, as an indicator of the premorbid background for gaming and other forms of behavioral addictions. The mechanisms of addictive behavior in rats reared in isolation (IS) were investigated by analyzing the extracellular release of dopamine in response to stimulation of the positive reinforcing zone. Before the experiments, male rats were kept in individual cages from the 21st day of birth to the 90th day. To study elements of addictive behavior, a variant of the Iowa Gambling Task in a 3-arm maze and a method of developing compulsive overeating using intermittent consumption of high-calorie foods were used. To study compulsive behavior, a marble test was used against the background of withdrawal from a high-calorie diet. Surgeries were performed to implant electrodes into the ventral tegmental area (VTA) and the nucleus accumbens in rats exhibiting elements of addictive behavior in the 3-arm maze. These animals were then trained to respond to VTA self-stimulation. Dopamine release was recorded telemetrically in freely moving rats in response to electrical stimulation of the VTA self-stimulation zone. Fast scan cyclic voltammetry was used to determine changes in dopamine levels in the extracellular environment of the nucleus accumbens. IS entered less into the arm with a high degree of probability but with a low reward, and entered more in the arm with a low degree of probability, but with a high reward, which is associated with the appearance of impulsivity in behavior. In the model of compulsive overeating, the number of approaches to the feeder in IS increased, and against the background of withdrawal of high-calorie food, IS were more active in the marble test. In IS exhibiting elements of addictive behavior in the 3-arm maze, the content of extracellular dopamine in response to electrical stimulation of the VTA self-stimulation zones did not reveal any differences compared to the control group of rats with addictive behavior in the maze. At the same time, IS exhibiting elements of addictive behavior in the maze showed a more pronounced dopamine response to a complex stimulus: a conditioned signal used during maze learning light + VTA stimulation. Thus, rearing in the IS causes an increase in dopamine release in the nucleus accumbens in response to stimulation of the positive reinforcement area associated with addictive behaviors: impulsivity and compulsivity. A conclusion is drawn about the prospects of studying the extracellular release of dopamine and assesses addictive behavior disorders caused by limited social contacts in ontogenesis.

Distinct catecholaminergic pathways projecting to hippocampal CA1 transmit contrasting signals during navigation in familiar and novel environments.

Neuromodulatory inputs to the hippocampus play pivotal roles in modulating synaptic plasticity, shaping neuronal activity, and influencing learning and memory. Recently, it has been shown that the main sources of catecholamines to the hippocampus, ventral tegmental area (VTA) and locus coeruleus (LC), may have overlapping release of neurotransmitters and effects on the hippocampus. Therefore, to dissect the impacts of both VTA and LC circuits on hippocampal function, a thorough examination of how these pathways might differentially operate during behavior and learning is necessary. We therefore utilized two-photon microscopy to functionally image the activity of VTA and LC axons within the CA1 region of the dorsal hippocampus in head-fixed male mice navigating linear paths within virtual reality (VR) environments. We found that within familiar environments some VTA axons and the vast majority of LC axons showed a correlation with the animals' running speed. However, as mice approached previously learned rewarded locations, a large majority of VTA axons exhibited a gradual ramping-up of activity, peaking at the reward location. In contrast, LC axons displayed a pre-movement signal predictive of the animal's transition from immobility to movement. Interestingly, a marked divergence emerged following a switch from the familiar to novel VR environments. Many LC axons showed large increases in activity that remained elevated for over a minute, while the previously observed VTA axon ramping-to-reward dynamics disappeared during the same period. In conclusion, these findings highlight distinct roles of VTA and LC catecholaminergic inputs in the dorsal CA1 hippocampal region. These inputs encode unique information, with reward information in VTA inputs and novelty and kinematic information in LC inputs, likely contributing to differential modulation of hippocampal activity during behavior and learning.

Distinct catecholaminergic pathways projecting to hippocampal CA1 transmit contrasting signals during navigation in familiar and novel environments

Neuromodulatory inputs to the hippocampus play pivotal roles in modulating synaptic plasticity, shaping neuronal activity, and influencing learning and memory. Recently, it has been shown that the main sources of catecholamines to the hippocampus, ventral tegmental area (VTA) and locus coeruleus (LC), may have overlapping release of neurotransmitters and effects on the hippocampus. Therefore, to dissect the impacts of both VTA and LC circuits on hippocampal function, a thorough examination of how these pathways might differentially operate during behavior and learning is necessary. We therefore utilized two-photon microscopy to functionally image the activity of VTA and LC axons within the CA1 region of the dorsal hippocampus in head-fixed male mice navigating linear paths within virtual reality (VR) environments. We found that within familiar environments some VTA axons and the vast majority of LC axons showed a correlation with the animals’ running speed. However, as mice approached previously learned rewarded locations, a large majority of VTA axons exhibited a gradual ramping-up of activity, peaking at the reward location. In contrast, LC axons displayed a pre-movement signal predictive of the animal’s transition from immobility to movement. Interestingly, a marked divergence emerged following a switch from the familiar to novel VR environments. Many LC axons showed large increases in activity that remained elevated for over a minute, while the previously observed VTA axon ramping-to-reward dynamics disappeared during the same period. In conclusion, these findings highlight distinct roles of VTA and LC catecholaminergic inputs in the dorsal CA1 hippocampal region. These inputs encode unique information, with reward information in VTA inputs and novelty and kinematic information in LC inputs, likely contributing to differential modulation of hippocampal activity during behavior and learning.

Multifunctional Neural Probes Enable Bidirectional Electrical, Optical, and Chemical Recording and Stimulation In Vivo.

Recording and modulation of neuronal activity enables the study of brain function in health and disease. While translational neuroscience relies on electrical recording and modulation techniques, mechanistic studies in rodent models leverage genetic precision of optical methods, such as optogenetics and fluorescent indicator imaging. In addition to electrical signal transduction, neurons produce and receive diverse chemical signals which motivate tools to probe and modulate neurochemistry. Although the past decade has delivered a wealth of technologies for electrophysiology, optogenetics, chemical sensing, and optical recording, combining these modalities within a single platform remains challenging. This work leverages materials selection and convergence fiber drawing to permit neural recording, electrical stimulation, optogenetics, fiber photometry, drug and gene delivery, and voltammetric recording of neurotransmitters within individual fibers. Composed of polymers and non-magnetic carbon-based conductors, these fibers are compatible with magnetic resonance imaging, enabling concurrent stimulation and whole-brain monitoring. Their utility is demonstrated in studies of the mesolimbic reward pathway by interfacing with the ventral tegmental area and nucleus accumbens in mice and characterizing the neurophysiological effects of a stimulant drug. This study highlights the potential of these fibers to probe electrical, optical, and chemical signaling across multiple brain regions in both mechanistic and translational studies.

Structural projections to the nucleus accumbens link to impulsive components of human risk preference

Abstract Functional responses in the Nucleus Accumbens (NAcc) to risk- and reward-related cues can predict real-life risk-taking behavior. Since NAcc activity depends on neurotransmission from connected brain regions, projections to the NAcc may also predict risk preference. To quantify risk preference, we employed latent variables previously derived in a comprehensive, independent study examining the psychometric structure of risk preference, which yielded a general risk preference factor as well as several specific factors, including a factor capturing impulsivity. Informed by previous work, we preregistered a set of hypotheses concerning the association between different risk preference factors and fractional anisotropy (or FA, which is sensitive to fiber coherence) for projections to the NAcc from Medial PreFrontal Cortex (MPFC), Anterior Insula, Amygdala, and an inferior tract from the Ventral Tegmental Area (iVTA). We tested our hypotheses in a community sample of 125 healthy human adults. As predicted, bilateral iVTA-NAcc tract FA showed a negative correlation with a psychometric factor that captured impulsivity, generalizing findings from prior research. Also as predicted, FA of the bilateral Amygdala-NAcc tract was positively associated with the impulsivity factor. Contrary to predictions, however, we observed no robust associations between the general risk preference factor and FA for projections from bilateral MPFC, right Anterior Insula, or bilateral Amygdala to the NAcc. Notably, exploratory unilateral analyses revealed an association between the general risk preference factor and left MPFC-NAcc tract FA. Taken together, these findings suggest that impulse control as a facet of risk preference maps onto specific neurobiological targets, while more general facets of risk preference may be supported by structural properties of lateral fronto-striatal projections. Although the exact associated functional mechanisms remain to be fully clarified, conNAcctomic approaches like the one presented here could pave the way for further research into the physiological foundations of risk preference and related constructs.

Effects of NMDA glutamatergic receptors pharmacological stimulation of the ventral tegmental area on the memory deficits induced by maternal deprivation

Maternal deprivation (MD) is a potent stressor during early life and can lead to behavioral changes during adulthood. Several neurochemical mechanisms underlying MD-induced stress have been proposed; among them is the damage caused to dopaminergic neurons in the ventral tegmental area (VTA). We hypothesized that pharmacological stimulation of dopaminergic neurons in VTA by the infusion of an N-Methyl-D-Aspartate (NMDA) receptors agonist (used considering the wide distribution of these glutamatergic receptors in the VTA neurons) can reverse MD-induced memory deficits. Here, we demonstrated that MD affects male and female rats distinctly, with females being more resilient to early-life stress. Furthermore, NMDA pharmacological stimulation of the VTA promotes object recognition (OR) memory persistence in male and female non-MD rats. In males, infusion of NMDA into the VTA immediately after the learning session reverses recognition memory deficits related to MD. Although MD female rats have not shown deficits in OR memory consolidation, the NMDA infusion immediately after the learning session promotes memory persistence. We verified that MD leads to memory deficits in adult male rats, while the females are resilient to early life stress. Furthermore, NMDA pharmacological stimulation of dopaminergic VTA neurons reveals the dopaminergic modulation of OR memory in MD rats, even in females that did not exhibit memory deficits.

Substantial projections from the lateral division of the lateral habenula to the dorsal raphe nucleus and from the lateral habenula to the contralateral ventral tegmental area

The lateral habenular nucleus (LHb) projects to the dorsal raphe nucleus (DRN) and ventral tegmental area (VTA). Prior studies have reported that the medial division of the LHb (LHb-m) mainly projects to the DRN, while the LHb mainly projects to the ipsilateral VTA; however, due to only a few studies of projection ratio analysis, the degree of projection of minor and major pathways remains unclear, and the potential significance of minor pathways may be overlooked. After injecting the retrograde tracer into the mice DRN, the proportion of labeled neurons was 63.50% in the LHb-m and 36.50% in the lateral division of the LHb (LHb-l). The proportion distributions of labeled neurons were 26.90% in the anterior LHb-m and 73.10% in the posterior LHb-m. When the retrograde tracer was injected into the VTA, the percentage of labeled neurons was 64.85% in the ipsilateral LHb and 35.15% in the contralateral LHb. The number of cells projecting from anterior and posterior ipsilateral LHb-m to the VTA varied among the individual injection sites. Our quantitative analysis with multiple subjects showed that the projections from LHb-l to DRN and from LHb to contralateral VTA were indeed minor pathways, however, they were substantial. These results provide an anatomical basis for the potential importance of minor pathways projected from the LHb to the VTA and DRN and for the difference in the densities of neurons projecting from the anterior and posterior LHb-m to the DRN.

Resting-State Functional Connectome Predicts Sleep Quality Two Months After the First Negative COVID-19 Antigen Test

BackgroundThe COVID-19 pandemic has led to long-term neurological and psychological effects, including sleep disturbances. While prior studies have identified altered brain function post-COVID-19, specific functional connectivity (FC) patterns predicting sleep quality after recovery remain unclear. This study aims to identify FC patterns associated with sleep quality two months after the first negative COVID-19 antigen test. MethodsUsing a connectome-based predictive modeling (CPM) approach, we identified the functional connectome regulating sleep quality based on a 164-region parcellation. Significant connections were analyzed using mediation models to examine their role in the relationship between anxiety, depression, and sleep. ResultsFC between the right cerebellar peduncle and the left VIII of the cerebellum, and between the left middle temporal pole (MTP) and left ventral tegmental area (VTA), significantly predicted Pittsburgh Sleep Quality Index (PSQI) scores for sleep disturbance two months post-recovery (q2 = 0.059, MSE = 0.154, p = 0.017, r = 0.350). Mediation analysis showed a significant indirect effect of FC between the left MTP and VTA on the relationship between generalized anxiety and sleep disturbances (indirect effect = 0.013, 95% CI = [0.002, 0.03], pfdr < 0.05). FC between the right dorsal raphe nucleus and ipsilateral regions—including occipital, parietal, and temporal areas—predicted PSQI scores for daytime dysfunction (q2 = 0.092, MSE = 0.678, p = 0.025, r = 0.342). ConclusionPost-COVID-19 brain connectivity and anxiety predict sleep quality. These findings highlight the potential for targeted therapeutic strategies to improve sleep and identify patients at risk for prolonged disturbances through FC biomarkers.

Functional Adaptation in the Brain Habenulo-Mesencephalic Pathway During Cannabinoid Withdrawal.

The mesolimbic reward system originating from dopamine neurons in the ventral tegmental area (VTA) of the midbrain shows a profound reduction in function during cannabinoid withdrawal. This condition may underlie aversive states that lead to compulsive drug seeking and relapse. The lateral habenula (LHb) exerts negative control over the VTA via the GABA rostromedial tegmental nucleus (RMTg), representing a potential convergence point for drug-induced opponent processes. We hypothesized that the LHb-RMTg pathway might be causally involved in the hypodopaminergic state during cannabinoid withdrawal. To induce Δ9-tetrahydrocannabinol (THC) dependence, adult male Sprague-Dawley rats were treated with THC (15 mg/kg, i.p.) twice daily for 6.5-7 days. Administration of the cannabinoid antagonist rimonabant (5 mg/kg, i.p.) precipitated a robust behavioral withdrawal syndrome, while abrupt THC suspension caused milder signs of abstinence. Extracellular single unit recordings confirmed a marked decrease in the discharge frequency and burst firing of VTA dopamine neurons during THC withdrawal. The duration of RMTg-evoked inhibition was longer in THC withdrawn rats. Additionally, the spontaneous activity of RMTg neurons and of LHb neurons was strongly depressed during cannabinoid withdrawal. These findings support the hypothesis that functional changes in the habenulo-mesencephalic circuit are implicated in the mechanisms underlying substance use disorders.

Optogenetic activation of mesencephalic projections to the nucleus accumbens shell impairs probabilistic reversal learning by disrupting learning from negative reinforcement.

Cognitive flexibility, the capacity to adapt behaviour to changes in the environment, is impaired in a range of brain disorders, including schizophrenia and Parkinson's disease. Putative neural substrates of cognitive flexibility include mesencephalic pathways to the ventral striatum (VS) and dorsomedial striatum (DMS), hypothesized to encode learning signals needed to maximize rewarded outcomes during decision-making. However, it is unclear whether mesencephalic projections to the ventral and dorsal striatum are distinct in their contribution to flexible reward-related learning. Here, rats acquired a two-choice spatial probabilistic reversal learning (PRL) task, reinforced on an 80%|20% basis (correct|incorrect responses) that assessed the flexibility of behaviour to repeated reversals of response-outcome contingencies. We report that optogenetic stimulation of projections from the ventral tegmental area (VTA) to the nucleus accumbens shell (NAcS) in the VS significantly impaired reversal learning when optical stimulation was temporally aligned with negative feedback (i.e., reward omission). VTA → NAcS stimulation during other phases of the behavioural task was without significant effect. Optogenetic stimulation of projection neurons from the substantia nigra (SN) to the DMS, aligned either with reward receipt or omission or prior to making a choice, had no significant effect on reversal learning. These findings are consistent with the notion that increased activity in the VTA → NAcS pathway disrupts behavioural flexibility by impairing learning from negative reinforcement.

Regional heterogeneity of cerebral blood flow immediately after the onset of ventricular pacing in anesthetized rats.

Selective distribution of cerebral blood flow (CBF) to vital brain regions likely occurs during rapid severe hypotension caused by tachyarrhythmia, but has not yet been demonstrated. In this study, we aimed to test the hypothesis that CBF is differentially preserved between brain regions depending on the degree of hypotension. In anesthetized rats, CBF was measured in the motor cortex (MC), medial prefrontal cortex, amygdala, thalamus, dorsal hypothalamus, hippocampus, ventral tegmental area, dorsolateral periaqueductal gray (dlPAG), and parabrachial nucleus (PB) by using laser-Doppler flowmetry. Ventricular pacing was performed for 30 s at 550-800 beats/min. The cerebrovascular CO2 response time and reactivity were evaluated during 5% CO2 exposure. During 1-4 s of ventricular pacing, mean arterial pressure (MAP) rapidly decreased, with minor changes in central venous and intracranial pressures. CBF was relatively well maintained in brain regions other than the MC (Ps ≤ 0.012) when moderate hypotension occurred (-34 mmHg ≤ ΔMAP ≤ -15 mmHg), whereas severe hypotension (-54 mmHg ≤ ΔMAP ≤ -35 mmHg) induced selective CBF distribution to regions other than the MC, thalamus, and dlPAG. The cerebrovascular CO2 response time/reactivity was rapid or high in the thalamus, dlPAG, and PB, which almost completely differed from the brain regions in which CBF was relatively maintained during pacing-induced severe hypotension. These results suggest that regional heterogeneity of CBF arises depending on the degree of tachyarrhythmia-induced hypotension. Clarifying the mechanisms and functions of CBF maintenance would be beneficial to syncope and cerebral ischemia management in patients with arrhythmia.

Dopaminergic modulation of visual attention in the prefrontal cortex

An essential cognitive ability that enables creatures to interpret pertinent information from their surroundings only is visual attention. The prefrontal cortex (PFC) is involved in modulating visual attention, and this review focuses on the dopaminergic aspects of this process. The PFC is crucial for top-down attention management, improving visual responses, and coordinating neural activity. This is especially true of the frontal eye field (FEF). Dopamine is an important neuromodulator that directly influences the PFC's visual signal processing by adjusting sensory input and the variability of neuronal response. The substantia nigra (SN) and ventral tegmental area (VTA) send dopaminergic pathways to the prefrontal cortex, where D1 and D2 receptors have different functions in attention regulation. Dopamine receptor modification has been shown in studies involving rodents and primates to have a major effect on visual attention and cognitive task performance. The exact mechanisms underlying dopamine's involvement in executive control are still unknown despite a great deal of research, which calls for more study, especially in rodent models. The present review highlights the significance of dopamine in the domain of high-level cognitive regulation and advocates for more investigation to clarify its mechanisms in visual attention.

Mechanical acupuncture at HT7 attenuates alcohol self-administration in rats by modulating neuroinflammation and altering mPFC-habenula-VTA circuit activity.

Alcohol use disorder is a chronic disorder with significant limitations in pharmacological treatments, necessitating the exploration of non-pharmacological interventions. We used a model of alcohol self-administration (10% v/v) to analyze behavioral, neurochemical, and signaling mechanisms. Our findings demonstrate that stimulation of the HT7 acupuncture point significantly decreased the frequency of active lever presses in rats self-administering alcohol (p < 0.05). Alcohol self-administration increased microglial activity and sigma 1 receptor expression in the habenula (Hb), while HT7 stimulation mitigated these effects, decreasing microglial activity and sigma 1 receptor levels (p < 0.05). Additionally, alcohol self-administration reduced brain-derived neurotrophic factor (BDNF) expression in the medial prefrontal cortex (mPFC) and increased tyrosine hydroxylase (TH) levels in the ventral tegmental area (VTA) (p < 0.05). HT7 stimulation reversed these alterations by increasing BDNF expression in the mPFC and decreasing TH levels in the VTA (p < 0.05). Further investigation revealed that BDNF microinjection into the mPFC inhibited sigma 1 receptor activity in the Hb, while microglial inhibition in the Hb decreased TH expression in the VTA (p < 0.05). The administration of the microglial inhibitor MINO to the Hb also reduced alcohol self-administration (p < 0.05). These results suggest that HT7 stimulation regulates the mPFC-Hb-VTA circuit, leading to decreased alcohol-seeking behavior. Our study demonstrates that HT7 acupuncture can modulate the mPFC-Hb-VTA circuit, providing a potential non-pharmacological treatment for alcohol-seeking behavior by influencing microglial activity, sigma 1 receptor expression, and TH levels. These findings contribute to a deeper understanding of the neural mechanisms underlying acupuncture's therapeutic effects on alcohol use disorder.

SARS-CoV-2 propagation to the TPH2-positive neurons in the ventral tegmental area induces cell death via GSK3β-dependent accumulation of phosphorylated tau.

COVID-19, an infectious disease caused by SARS-CoV-2, was declared a pandemic by the WHO in 2020. Psychiatric symptoms including sleep disturbance, memory impairment, and depression are associated with SARS-CoV-2 infection. These symptoms are causes long-term mental and physical distress in recovering patients; however, the underlying mechanism is unclear. In this study, we determined the effects of SARS-CoV-2 infection on brain tissue using k18hACE2 mice. Using brain tissue from 18hACE2 mice infected with SARS-CoV-2 through intranasal administration, SARS-CoV-2 spike protein and RNA were analyzed by immunohistochemical staining and in-situ hybridization. Immunohistochemical analysis revealed that Tryptophan hydroxylase 2 (TPH2)-positive cells and SARS-CoV-2 spike protein were co-localized in the ventral tegmental area of SARS-CoV-2-infected mice. We observed decreased TPH2 expression and increased accumulation of phosphorylated tau protein and Phospho-Histone H2A.X (γH2AX) expression in the ventral tegmental region. In addition, activation of glycogen synthase kinase 3β (GSK3β) was induced by SARS-CoV-2 infection. Overall, our results suggest that SARS-CoV-2 infection of TPH2-positive cells in the ventral tegmental area induces neuronal cell death through increased accumulation of phosphorylated tau. Attenuation of the GSK3β pathway and decreased serotonin synthesis through suppression of TPH2 expression may contribute to the development of neurological symptoms.

Proportion and distribution of neurotransmitter-defined cell types in the ventral tegmental area and substantia nigra pars compacta

Most studies on the ventral tegmental area (VTA) and substantia nigra pars compacta (SNc) have focused on dopamine neurons and their role in processes such as motivation, learning, movement, and associated disorders such as addiction and Parkinson's disease. However there has been increasing attention on other VTA and SNc cell types that release GABA, glutamate, or a combination of neurotransmitters. Yet the relative distributions and proportions of neurotransmitter-defined cell types across VTA and SNc has remained unclear. Here, we used fluorescent in situ hybridization in male and female mice to label VTA and SNc neurons that expressed mRNA encoding the canonical vesicular transporters for dopamine, GABA, or glutamate: vesicular monoamine transporter (VMAT2), vesicular GABA transporter (VGAT), and vesicular glutamate transporter (VGLUT2). Within VTA, we found that no one type was particularly more abundant, instead we observed similar numbers of VMAT2+ (44 %), VGAT+ (37 %) and VGLUT2+ (41 %) neurons. In SNc we found that a slight majority of neurons expressed VMAT2 (54 %), fewer were VGAT+ (42 %), and VGLUT2+ neurons were least abundant (16 %). Moreover, 20 % of VTA neurons and 10 % of SNc neurons expressed more than one vesicular transporter, including 45 % of VGLUT2+ neurons. We also assessed within VTA and SNc subregions and found remarkable heterogeneity in cell-type composition. And by quantifying density across both anterior-posterior and medial-lateral axes we generated heatmaps to visualize the distribution of each cell type. Our data complement recent single-cell RNAseq studies and support a more diverse landscape of neurotransmitter-defined cell types in VTA and SNc than is typically appreciated.

Reward system activation improves recovery from acute myocardial infarction

Abstract Introduction Psychological processes play a crucial role in the recovery from acute myocardial infarction (AMI), yet the underlying mechanisms of these effects remain elusive. Here, we focused on the reward system, which mediates positively valenced emotions, motivation, and expectation and is based mainly on dopaminergic neurotransmission from the ventral tegmental area (VTA). Purpose The study examines the impact of activating dopaminergic neurons in the VTA following AMI in mice, aiming to understand the extent and mechanisms through which motivational brain network contribute to cardiac recovery process. Methods We used Designer Receptor Exclusively Activated by Designer Drugs (DREADDs) to target neuronal activity. We performed an AMI model and assessed cardiac function using cardiac magnetic resonance (CMR). We used histology, immunohistochemistry, proteomic analysis, ELISA, reverse transcription-PCR, endothelial tube formation assay, and pseudorabies-virus neuronal tracing to investigate the mechanism. Results Chemogenetic activation of dopaminergic neurons in the VTA significantly modified the remodeling processes by reducing scar tissue (Fig. 1a) and increased vascularization (Fig. 1b) 15 days following AMI, leading to improved left-ventricular performance compared to control (Fig. 1c). These effects were mediated through several physiological mechanisms, including alterations in immune activity, and reduced adrenergic inputs to the liver. We further demonstrate an anatomical connection between the VTA and the liver that follows AMI manifested by altered transcription of complement component 3 (C3). We established the essential role of C3 in endothelial tube formation in vitro and its necessity in the beneficial effects of VTA activation on the recovery from AMI in vivo (Fig.2). Conclusion These findings establish a causal connection between a motivational brain network and recovery from AMI, introducing potential new therapeutic avenues for intervention.Effects of VTA activation on cardiac recMechanism of VTA effects

Exploring distinct and joint contributions of the locus coeruleus and the substantia nigra/ventral tegmental area complex to reward and valence processing using high-resolution fMRI

Abstract Dopaminergic neurons in the substantia nigra and the ventral tegmental area (SN/VTA) are classically viewed as key mediators in reward processing, while noradrenergic cells in the locus coeruleus (LC) are thought to modulate (negative) saliency processing. However, this conventional distinction is being revised by more recent research in animals. To explore the respective contributions of both the LC and SN/VTA in reward and valence processing in humans, we assessed fMRI data during stimulus encoding and response phase of a rewarded emotion-discrimination task (n = 38). Participants responded significantly faster to reward predicting and negative valence stimuli compared with their non-salient counterparts. LC activity was overall higher during trials involving reward prospect, and in particular for reward trials featuring positive valence, demonstrating an additive effect of reward and positive valence in LC. Moreover, LC activity was differentially increased for negative compared with positive valence in the response phase, indexing its role in invigorating responses to negative events. The SN/VTA showed increased activity in the response phase of reward trials (neutral valence) and negative valence trials (no reward), which aligns with coding relative saliency of these events in their respective contexts. LC modulations were accompanied by covariations in occipital cortex, suggesting noradrenergic contributions to visual prioritization of salient events. The findings underscore the sensitivity of both LC and SN/VTA to reward prospects and negative valence, challenging the dominant view of SN/VTA’s involvement in merely positive events and emphasizing their essential role in action invigoration above and beyond mere stimulus encoding. The intricate roles of the DA and NA system in reward and emotional valence processing in humans warrant further exploration and validation, given the limitations inherent to neuroimaging of deep brain structures.