Ventral Tegmental Area Neurons Research Articles

Ketamine and Major Ketamine Metabolites Function as Allosteric Modulators of Opioid Receptors.

Ketamine is a glutamate receptor antagonist that was developed over 50 years ago as an anesthetic agent. At subanesthetic doses, ketamine and some metabolites are analgesics and fast-acting antidepressants, presumably through targets other than glutamate receptors. We tested ketamine and its metabolites for activity as allosteric modulators of opioid receptors expressed as recombinant receptors in heterologous systems and with native receptors in rodent brain; signaling was examined by measuring GTP binding, β-arrestin recruitment, MAPK activation, and neurotransmitter release. Although micromolar concentrations of ketamine alone had weak agonist activity at μ opioid receptors, the combination of submicromolar concentrations of ketamine with endogenous opioid peptides produced robust synergistic responses with statistically significant increases in efficacies. All three opioid receptors (μ, δ, and κ) showed synergism with submicromolar concentrations of ketamine and either methionine-enkephalin (Met-enk), leucine-enkephalin (Leu-enk), and/or dynorphin A17 (Dyn A17), albeit the extent of synergy was variable between receptors and peptides. S-ketamine exhibited higher modulatory effects compared with R-ketamine or racemic ketamine, with ∼100% increase in efficacy. Importantly, the ketamine metabolite 6-hydroxynorketamine showed robust allosteric modulatory activity at μ opioid receptors; this metabolite is known to have analgesic and antidepressant activity but does not bind to glutamate receptors. Ketamine enhanced potency and efficacy of Met-enkephalin signaling both in mouse midbrain membranes and in rat ventral tegmental area neurons as determined by electrophysiology recordings in brain slices. Taken together, these findings support the hypothesis that some of the therapeutic effects of ketamine and its metabolites are mediated by directly engaging the endogenous opioid system. SIGNIFICANCE STATEMENT: This study found that ketamine and its major biologically active metabolites function as potent allosteric modulators of μ, δ, and κ opioid receptors, with submicromolar concentrations of these compounds synergizing with endogenous opioid peptides, such as enkephalin and dynorphin. This allosteric activity may contribute to ketamine's therapeutic effectiveness for treating acute and chronic pain and as a fast-acting antidepressant drug.

Neuronal activity in the ventral tegmental area during goal-directed navigation recorded by low-curvature microelectrode arrays

Navigating toward destinations with rewards is a common behavior among animals. The ventral tegmental area (VTA) has been shown to be responsible for reward coding and reward cue learning, and its response to other variables, such as kinematics, has also been increasingly studied. These findings suggest a potential relationship between animal navigation behavior and VTA activity. However, the deep location and small volume of the VTA pose significant challenges to the precision of electrode implantation, increasing the uncertainty of measurement results during animal navigation and thus limiting research on the role of the VTA in goal-directed navigation. To address this gap, we innovatively designed and fabricated low-curvature microelectrode arrays (MEAs) via a novel backside dry etching technique to release residual stress. Histological verification confirmed that low-curvature MEAs indeed improved electrode implantation precision. These low-curvature MEAs were subsequently implanted into the VTA of the rats to observe their electrophysiological activity in a freely chosen modified T-maze. The results of the behavioral experiments revealed that the rats could quickly learn the reward probability corresponding to the left and right paths and that VTA neurons were deeply involved in goal-directed navigation. Compared with those in no-reward trials, VTA neurons in reward trials presented a significantly greater firing rate and larger local field potential (LFP) amplitude during the reward-consuming period. Notably, we discovered place fields mapped by VTA neurons, which disappeared or were reconstructed with changes in the path–outcome relationship. These results provide new insights into the VTA and its role in goal-directed navigation. Our designed and fabricated low-curvature microelectrode arrays can serve as a new device for precise deep brain implantation in the future.

Chronic ethanol exposure in mice evokes pre- and postsynaptic deficits in GABAergic transmission in ventral tegmental area GABA neurons.

GABAergic neurons in mouse ventral tegmental area (VTA) exhibit elevated activity during withdrawal following chronic ethanol exposure. While increased glutamatergic input and decreased GABAA receptor sensitivity have been implicated, the impact of inhibitory signaling in VTA GABA neurons has not been fully addressed. We used electrophysiological and ultrastructural approaches to assess the impact of chronic intermittent ethanol vapour exposure in mice on GABAergic transmission in VTA GABA neurons during withdrawal. We used CRISPR/Cas9 ablation to mimic a somatodendritic adaptation involving the GABAB receptor (GABABR) in ethanol-naïve mice to investigate its impact on anxiety-related behaviour. The frequency of spontaneous inhibitory postsynaptic currents was reduced in VTA GABA neurons following chronic ethanol treatment and this was reversed by GABABR inhibition, suggesting chronic ethanol strengthens the GABABR-dependent suppression of GABAergic input to VTA GABA neurons. Similarly, paired-pulse depression of GABAA receptor-dependent responses evoked by optogenetic stimulation of nucleus accumbens inputs from ethanol-treated mice was reversed by GABABR inhibition. Somatodendritic currents evoked in VTA GABA neurons by GABABR activation were reduced following ethanol exposure, attributable to the suppression of GIRK (Kir3) channel activity. Mimicking this adaptation enhanced anxiety-related behaviour in ethanol-naïve mice. Chronic ethanol weakens the GABAergic regulation of VTA GABA neurons in mice via pre- and postsynaptic mechanisms, likely contributing to their elevated activity during withdrawal and expression of anxiety-related behaviour. As anxiety can promote relapse during abstinence, interventions targeting VTA GABA neuron excitability could represent new therapeutic strategies for treatment of alcohol use disorder.

Receptor and metabolic insights on the ability of caffeine to prevent alcohol-induced stimulation of mesolimbic dopamine transmission

The consumption of alcohol and caffeine affects the lives of billions of individuals worldwide. Although recent evidence indicates that caffeine impairs the reinforcing properties of alcohol, a characterization of its effects on alcohol-stimulated mesolimbic dopamine (DA) function was lacking. Acting as the pro-drug of salsolinol, alcohol excites DA neurons in the posterior ventral tegmental area (pVTA) and increases DA release in the nucleus accumbens shell (AcbSh). Here we show that caffeine, via antagonistic activity on A2A adenosine receptors (A2AR), prevents alcohol-dependent activation of mesolimbic DA function as assessed, in-vivo, by brain microdialysis of AcbSh DA and, in-vitro, by electrophysiological recordings of pVTA DA neuronal firing. Accordingly, while the A1R antagonist DPCPX fails to prevent the effects of alcohol on DA function, both caffeine and the A2AR antagonist SCH 58261 prevent alcohol-dependent pVTA generation of salsolinol and increase in AcbSh DA in-vivo, as well as alcohol-dependent excitation of pVTA DA neurons in-vitro. However, caffeine also prevents direct salsolinol- and morphine-stimulated DA function, suggesting that it can exert these inhibitory effects also independently from affecting alcohol-induced salsolinol formation or bioavailability. Finally, untargeted metabolomics of the pVTA showcases that caffeine antagonizes alcohol-mediated effects on molecules (e.g. phosphatidylcholines, fatty amides, carnitines) involved in lipid signaling and energy metabolism, which could represent an additional salsolinol-independent mechanism of caffeine in impairing alcohol-mediated stimulation of mesolimbic DA transmission. In conclusion, the outcomes of this study strengthen the potential of caffeine, as well as of A2AR antagonists, for future development of preventive/therapeutic strategies for alcohol use disorder.

Monosynaptic inputs to ventral tegmental area glutamate and GABA co-transmitting neurons.

A unique population of ventral tegmental area (VTA) neurons co-transmits glutamate and GABA. However, the circuit inputs to VTA VGluT2+VGaT+ neurons are unknown, limiting our understanding of their functional capabilities. By coupling monosynaptic rabies tracing with intersectional genetic targeting in male and female mice, we found that VTA VGluT2+VGaT+ neurons received diverse brain-wide inputs. The largest numbers of monosynaptic inputs to VTA VGluT2+VGaT+ neurons were from superior colliculus, lateral hypothalamus, midbrain reticular nucleus, and periaqueductal gray, whereas the densest inputs relative to brain region volume were from dorsal raphe nucleus, lateral habenula, and ventral tegmental area. Based on these and prior data, we hypothesized that lateral hypothalamus and superior colliculus inputs were glutamatergic neurons. Optical activation of glutamatergic lateral hypothalamus neurons activated VTA VGluT2+VGaT+ neurons regardless of stimulation frequency and resulted in flee-like ambulatory behavior. In contrast, optical activation of glutamatergic superior colliculus neurons activated VTA VGluT2+VGaT+ neurons for a brief period of time at high stimulation frequency and resulted in head rotation and arrested ambulatory behavior (freezing). Stimulation of glutamatergic lateral hypothalamus neurons, but not glutamatergic superior colliculus neurons, was associated with VTA VGluT2+VGaT+ footshock-induced activity. In addition, inhibition of lateral hypothalamus glutamatergic neurons disrupted VTA VGluT2+VGaT+ tailshock-induced activity. We interpret these results such that inputs to VTA VGluT2+VGaT+ neurons may integrate diverse signals related to the detection and processing of motivationally-salient outcomes.Significance Statement VTA glutamate neurons have roles in motivated behavior and unique neurotransmission capabilities. A specific VTA glutamate neuron subtype, those that co-transmit glutamate and GABA, have unique outcome signaling properties compared to other VTA cell-types. However, the circuits that regulate these neurons are unclear. We identified the whole-brain inputs to VTA glutamate and GABA co-transmitting neurons. We also identify two distinct glutamatergic inputs that activate VTA glutamate and GABA co-transmitting neurons and result in different behavioral repertoires suggestive of threat processing. Together, these results provide novel insights into the circuit and cell-type specific influences on VTA glutamate and GABA co-transmitting neuronal activity as integrators of motivationally salient outcomes.

Expression of sensitized β2 nAChR subunits in VTA neurons enhances intravenous nicotine self-administration in male rats

Ventral tegmental area (VTA) nicotinic acetylcholine receptors (nAChRs) are important for nicotine reinforcement. To determine whether and to what extent these receptors are sufficient for nicotine reinforcement, we expressed β2Leu9′Ser (i.e. sensitized) nAChR subunits in the VTA of adult male rats and assessed the nicotine dose-response relationship in intravenous self-administration (SA). β2Leu9′Ser rats self-administered nicotine doses 50–100 fold lower than the lowest doses that control rats would respond for. Expression of WT β2 subunits confirmed that this enhanced sensitivity to nicotine was due to the Leu9′Ser mutation in β2. Higher unit doses were associated with strong escalation in β2Leu9′Ser rats over 17 fixed ratio sessions. Escalation was minimal or absent in control rats at the same unit doses. In progressive ratio SA, β2Leu9′Ser rats exhibited higher breakpoints than control rats when the nicotine unit dose was 1.5 μg/kg/inf or higher. In intermittent access SA, β2Leu9′Ser rats exhibited response patterns very similar to control rats. By adding nicotine dose-response data, progressive ratio assays, and intermittent access results that rule out stereotypy, these data significantly extend our previous finding that nicotine activation of the mesolimbic dopamine pathway is sufficient for nicotine reinforcement.

Upregulation of HCN2 in ventral tegmental area is involved in morphine-induced conditioned place preference in rats.

Morphine is an opioid commonly used to treat pain in clinic, but it also has the potential to be highly addictive, which can lead to abuse. Despite these known risks, the cellular and molecular mechanism of morphine conditioned place preference (CPP) is still unclear. In this study, using a rat model of chronic morphine administration, we found that compared with the control group, the mRNA and protein expression of HCN2 channel in the ventral tegmental area (VTA) were upregulated. Further immunofluorescence analysis showed that the fluorescence intensity of HCN2 channel of VTA dopaminergic neurons in morphine group was significantly enhanced, while the patch clamp recording of brain slices showed that both the magnitude and the density of Ih (HCN channel current) of VTA neurons were significantly increased. Moreover, intra-VTA infusion of ZD7288, a selective inhibitor of HCN channel, into rats of the morphine group decreased morphine CPP. Taken together, our results show that chronic morphine administration induces an upregulation of HCN2 in VTA dopamine neurons, while HCN inhibition reduces morphine CPP, suggesting that HCN channel may be a potential target for the treatment of morphine addiction.

Tyrosine hydroxylase expression and neuronal loss in the male and female adolescent ventral tegmental area

Adolescence is a critical period of development characterized by numerous behavioral and neuroanatomical changes. While studies of adolescent neurodevelopment typically compare adolescent age groups with young adults, there are fewer studies that assess developmental trajectories within the adolescent period. In the adolescent prefrontal cortex, some maturational changes take place linearly/chronologically, while others are associated specifically with pubertal onset. The adolescent ventral tegmental area (VTA), a primary source of forebrain dopamine, is relatively understudied during this period. In the present study, dopamine neuron number, total neuron number and tyrosine hydroxylase expression are assessed in the male and female rat VTA at three timepoints: postnatal day(P) 30 (pre-pubertal), P40 (post-pubertal for females, pre-pubertal for males) and P60 (post-pubertal). There was a non-significant trend for a reduction in total VTA neuron number between P30 and P60, but there was a significant reduction in dopamine neuron number across age. The expression of tyrosine hydroxylase did not change with age. However, in a second cohort of subjects, brain tissue was collected pre-pubertal, from recently post-pubertal males and females, and young adults. In this cohort, there was a sex-specific and transient decrease in tyrosine hydroxylase expression in recently post-pubertal males. These results suggest a selective pruning of VTA dopamine cells between early adolescence and young adulthood, while pubertal onset may coincide with a rapid maturation of these neurons. These findings may have implications for psychiatric disorders associated with dopamine dysfunction that tend to manifest during adolescence.

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. 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.

Chronic Social Defeat Stress Induces Pathway-Specific Adaptations at Lateral Habenula Neuronal Outputs.

The lateral habenula (LHb) has emerged as a pivotal brain region implicated in depression, displaying hyperactivity in human and animal models of depression. While the role of LHb efferents in depressive disorders has been acknowledged, the specific synaptic alterations remain elusive. Here, employing optogenetics, retrograde tracing, and ex vivo whole-cell patch-clamp techniques, we investigated synaptic transmission in male mice subjected to chronic social defeat stress (CSDS) at three major LHb neuronal outputs: the dorsal raphe nucleus (DRN), the ventral tegmental area (VTA), and the rostromedial tegmental nucleus (RMTg). Our findings uncovered distinct synaptic adaptations in LHb efferent circuits in response to CSDS. Specifically, CSDS induced in susceptible mice postsynaptic potentiation and postsynaptic depression at the DRN and VTA neurons, respectively, receiving excitatory inputs from the LHb, while CSDS altered presynaptic transmission at the LHb terminals in RMTg in both susceptible and resilient mice. Moreover, whole-cell recordings at projection-defined LHb neurons indicate decreased spontaneous activity in VTA-projecting LHb neurons, accompanied by an imbalance in excitatory-inhibitory inputs at the RMTg-projecting LHb neurons. Collectively, these novel findings underscore the circuit-specific alterations in LHb efferents following chronic social stress, shedding light on potential synaptic adaptations underlying stress-induced depressive-like states.

The dopaminergic system promotes neprilysin-mediated degradation of amyloid-β in the brain.

Deposition of amyloid-β (Aβ) in the brain can impair neuronal function and contribute to cognitive decline in Alzheimer's disease (AD). Here, we found that dopamine and the dopamine precursor levodopa (also called l-DOPA) induced Aβ degradation in the brain. Chemogenetic approaches in mice revealed that the activation of dopamine release from ventral tegmental area (VTA) neurons increased the abundance and activity of the Aβ-degrading enzyme neprilysin and reduced the amount of Aβ deposits in the prefrontal cortex in a neprilysin-dependent manner. Aged mice had less dopamine and neprilysin in the anterior cortex, a decrease that was accentuated in AD model mice. Treating AD model mice with levodopa reduced Aβ deposition and improved cognitive function. These observations demonstrate that dopamine promotes brain region-specific, neprilysin-dependent degradation of Aβ, suggesting that dopamine-associated strategies have the potential to treat this aspect of AD pathology.

Voluntary Exercise Ameliorates Chronic Ethanol Withdrawal-Induced Adaptations of Opioid Receptor Expression in the Nucleus Accumbens, Dopamine Release, and Ethanol Consumption.

Exercise has increasingly been recognized as an adjunctive therapy for alcohol-use disorder (AUD), yet our understanding of its underlying neurological mechanisms remains limited. This knowledge gap impedes the development of evidence-based exercise guidelines for AUD treatment. Chronic ethanol (EtOH) exposure has been shown to upregulate and sensitize kappa opioid receptors (KORs) in the nucleus accumbens (NAc), which is innervated by dopamine (DA) neurons in the midbrain ventral tegmental area (VTA), which may contribute to AUD-related behaviors. In this study, we investigated the impact of voluntary exercise in EtOH-dependent mice on EtOH consumption, KOR and delta opioid receptor (DOR) expression in the NAc and VTA, and functional effects on EtOH-induced alterations in DA release in the NAc. Our findings reveal that voluntary exercise reduces EtOH consumption, reduces KOR and enhances DOR expression in the NAc, and modifies EtOH-induced adaptations in DA release, suggesting a competitive interaction between exercise-induced and EtOH-induced alterations in KOR expression. We also found changes to DOR expression in the NAc and VTA with voluntary exercise but no significant changes to DA release. These findings elucidate the complex interplay of AUD-related neurobiological processes, highlighting the potential for exercise as a therapeutic intervention for AUD.

Dopamine neurons drive spatiotemporally heterogeneous striatal dopamine signals during learning

Environmental cues, through Pavlovian learning, become conditioned stimuli that invigorate and guide animals toward rewards. Dopamine (DA) neurons in the ventral tegmental area (VTA) and substantia nigra (SNc) are crucial for this process, via engagement of a reciprocally connected network with their striatal targets. Critically, it remains unknown how dopamine neuron activity itself engages dopamine signals throughout the striatum, across learning. Here, we investigated how optogenetic Pavlovian cue conditioning of VTA or SNc dopamine neurons directs cue-evoked behavior and shapes subregion-specific striatal dopamine dynamics. We used a fluorescent biosensor to monitor dopamine in the nucleus accumbens (NAc) core and shell, dorsomedial striatum (DMS), and dorsolateral striatum (DLS). We demonstrate spatially heterogeneous, learning-dependent dopamine changes across striatal regions. Although VTA stimulation-evoked robust dopamine release in NAc core, shell, and DMS, predictive cues preferentially recruited dopamine release in NAc core, starting early in training, and DMS, late in training. Negative prediction error signals, reflecting a violation in the expectation of dopamine neuron activation, only emerged in the NAc core and DMS. Despite the development of vigorous movement late in training, conditioned dopamine signals did not emerge in the DLS, even during Pavlovian conditioning with SNc dopamine neuron activation, which elicited robust DLS dopamine release. Together, our studies show a broad dissociation in the fundamental prediction and reward-related information generated by VTA and SNc dopamine neuron populations and signaled by dopamine across the striatum. Further, they offer new insight into how larger-scale adaptations across the striatal network emerge during learning to coordinate behavior.

Receptor and metabolic insights on the ability of caffeine to prevent alcohol-induced stimulation of mesolimbic dopamine transmission.

The consumption of alcohol and caffeine affects the lives of billions of individuals worldwide. Although recent evidence indicates that caffeine impairs the reinforcing properties of alcohol, a characterization of its effects on alcohol-stimulated mesolimbic dopamine (DA) function was lacking. Acting as the pro-drug of salsolinol, alcohol excites DA neurons in the posterior ventral tegmental area (pVTA) and increases DA release in the nucleus accumbens shell (AcbSh). Here we show that caffeine, via antagonistic activity on A2A adenosine receptors (A2AR), prevents alcohol-dependent activation of mesolimbic DA function as assessed, in-vivo, by brain microdialysis of AcbSh DA and, in-vitro, by electrophysiological recordings of pVTA DA neuronal firing. Accordingly, while the A1R antagonist DPCPX fails to prevent the effects of alcohol on DA function, both caffeine and the A2AR antagonist SCH 58261 prevent alcohol-dependent pVTA generation of salsolinol and increase in AcbSh DA in-vivo, as well as alcohol-dependent excitation of pVTA DA neurons in-vitro. However, caffeine also prevents direct salsolinol- and morphine-stimulated DA function, suggesting that it can exert these inhibitory effects also independently from affecting alcohol-induced salsolinol formation or bioavailability. Finally, untargeted metabolomics of the pVTA showcases that caffeine antagonizes alcohol-mediated effects on molecules (e.g. phosphatidylcholines, fatty amides, carnitines) involved in lipid signaling and energy metabolism, which could represent an additional salsolinol-independent mechanism of caffeine in impairing alcohol-mediated stimulation of mesolimbic DA transmission. In conclusion, the outcomes of this study strengthen the potential of caffeine, as well as of A2AR antagonists, for future development of preventive/therapeutic strategies for alcohol use disorder.

Ventral tegmental area interneurons revisited: GABA and glutamate projection neurons make local synapses.

The ventral tegmental area (VTA) contains projection neurons that release the neurotransmitters dopamine, GABA, and/or glutamate from distal synapses. VTA also contains GABA neurons that synapse locally on to VTA dopamine neurons, synapses widely credited to a population of so-called VTA interneurons. Interneurons in cortex, striatum, and elsewhere have well-defined morphological features, physiological properties, and molecular markers, but such features have not been clearly described in VTA. Indeed, there is scant evidence that local and distal synapses originate from separate populations of VTA GABA neurons. In this study we tested whether several markers expressed in non-dopamine VTA neurons are selective markers of interneurons, defined as neurons that synapse locally but not distally. Challenging previous assumptions, we found that VTA neurons genetically defined by expression of parvalbumin, somatostatin, neurotensin, or mu-opioid receptor project to known VTA targets including nucleus accumbens, ventral pallidum, lateral habenula, and prefrontal cortex. Moreover, we provide evidence that VTA GABA and glutamate projection neurons make functional inhibitory or excitatory synapses locally within VTA. These findings suggest that local collaterals of VTA projection neurons could mediate functions prior attributed to VTA interneurons. This study underscores the need for a refined understanding of VTA connectivity to explain how heterogeneous VTA circuits mediate diverse functions related to reward, motivation, or addiction.

Spatial localization of hippocampal replay requires dopamine signaling.

Sequenced reactivations of hippocampal neurons called replays, concomitant with sharp-wave ripples in the local field potential, are critical for the consolidation of episodic memory, but whether replays depend on the brain's reward or novelty signals is unknown. Here we combined chemogenetic silencing of dopamine neurons in ventral tegmental area (VTA) and simultaneous electrophysiological recordings in dorsal hippocampal CA1, in freely behaving rats experiencing changes to reward magnitude and environmental novelty. Surprisingly, VTA silencing did not prevent ripple increases where reward was increased, but caused dramatic, aberrant ripple increases where reward was unchanged. These increases were associated with increased reverse-ordered replays. On familiar tracks this effect disappeared, and ripples tracked reward prediction error, indicating that non-VTA reward signals were sufficient to direct replay. Our results reveal a novel dependence of hippocampal replay on dopamine, and a role for a VTA-independent reward prediction error signal that is reliable only in familiar environments.

The Neuroscience of Motivated Memory

Motivation is essential to memory because it ensures important memories are prioritized for future behavior. Recent studies have looked into the multi-faceted relationship between motivation and memory; other biological evidence which links motivation and memory has given rise to an examination of the underlying neurobiological basis that facilitates this connection. The neurotransmitter dopamine is strongly associated with motivation. Particularly, midbrain dopamine neurons in the reward-regulating ventral tegmental area which project to the hippocampus are well-positioned to enable a motivational influence on memory formation. This prompts an examination of the differing effects of extrinsic and intrinsic motivation on memory encoding and consolidation, as well evidence supporting the crucial role of coordinated activity between the mesolimbic pathway and the hippocampus. In this review, we first look into hypotheses about the biological processes through which dopamine is associated with reward motivation and memory. We then examine and summarize the neurobiologic hypotheses and recent evidence on the interplay between motivation and declarative memory with a focus on dopamine as the linking mechanism.

C57BL/6J offspring mice reared by a single-mother exhibit, compared to mice reared in a biparental parenting structure, distinct neural activation patterns and heightened ethanol-induced anxiolysis.

Parenting experiences with caregivers play a key role in neurodevelopment. We recently reported that adolescents reared by a single-mother (SM) display an anxiety-prone phenotype and drink more alcohol, compared to peers derived from a biparental (BP) rearing condition. To investigate if SM and BP offspring infant mice exhibit differential sensitivity to ethanol-induced locomotor activity and differential activity patterns in brain areas related to anxiety response. We also analyzed anxiety response and ethanol-induced anxiolysis in SM and BP adolescents. Mice reared in SM or BP conditions were assessed for (a) ethanol-induced locomotor activity at infancy, (b) central expression of Fos-like proteins (likely represented mostly by FosB, a transcription factor that accumulates after chronic stimuli exposure and serves as a molecular marker of neural plasticity) and cathecolaminergic activity, and (c) anxiety-like behavior and ethanol-induced anxiolysis in adolescence. Infant mice were sensitive to the stimulating effects of 2.0g/kg alcohol, regardless parenting structure. SM mice exhibited, relative to BP mice, a significantly greater number of Fos-like positive cells in the central amygdala and basolateral amygdala nuclei. Ethanol treatment, but not parenting condition, induced greater activation of dopaminergic neurons in ventral tegmental area. SM, but not BP, adolescent mice were sensitive to ethanol-induced anxiolysis. These results highlight the complex relationship between parenting experiences and neurodevelopment. The SM parenting may result in greater neural activation patterns in brain areas associated with anxiety response, potentially contributing to increased basal anxiety and alcohol sensitivity.

The avBNSTGABA–VTA and avBNSTGABA–DRN pathways are respectively involved in the regulation of anxiety-like behaviors in parkinsonian rats

The anteroventral bed nucleus of stria terminalis (avBNST) is a key brain region which involves negative emotional states, such as anxiety. The most neurons in the avBNST are GABAergic, and it sends GABAergic projections to the ventral tegmental area (VTA) and the dorsal raphe nucleus (DRN), respectively. The VTA and DRN contain dopaminergic and serotonergic cell groups in the midbrain which regulate anxiety-like behaviors. However, it is unclear the role of GABAergic projections from the avBNST to the VTA and the DRN in the regulation of anxiety-like behaviors, particularly in Parkinson's disease (PD)-related anxiety. In the present study, unilateral 6-hydroxydopamine (6-OHDA) lesions of the substantia nigra pars compacta in rats induced anxiety-like behaviors, and decreased level of dopamine (DA) in the basolateral amygdala (BLA). Chemogenetic activation of avBNSTGABA–VTA or avBNSTGABA–DRN pathway induced anxiety-like behaviors and decreased DA or 5-HT release in the BLA in sham and 6-OHDA rats, while inhibition of avBNSTGABA–VTA or avBNSTGABA–DRN pathway produced anxiolytic-like effects and increased level of DA or 5-HT in the BLA. These findings suggest that avBNST inhibitory projections directly regulate dopaminergic neurons in the VTA and serotonergic neurons in the DRN, and the avBNSTGABA–VTA and avBNSTGABA–DRN pathways respectively exert impacts on PD-related anxiety-like behaviors.

A septal-ventral tegmental area circuit drives exploratory behavior

To survive, animals need to balance their exploratory drive with their need for safety. Subcortical circuits play an important role in initiating and modulating movement based on external demands and the internal state of the animal; however, how motivation and onset of locomotion are regulated remain largely unresolved. Here, we show that a glutamatergic pathway from the medial septum and diagonal band of Broca (MSDB) to the ventral tegmental area (VTA) controls exploratory locomotor behavior in mice. Using a self-supervised machine learning approach, we found an overrepresentation of exploratory actions, such as sniffing, whisking, and rearing, when this projection is optogenetically activated. Mechanistically, this role relies on glutamatergic MSDB projections that monosynaptically target a subset of both glutamatergic and dopaminergic VTA neurons. Taken together, we identified a glutamatergic basal forebrain to midbrain circuit that initiates locomotor activity and contributes to the expression of exploration-associated behavior.