scholarly journals Tonic activity in lateral habenula neurons promotes disengagement from reward-seeking behavior

2021 ◽  
Author(s):  
Brianna J. Sleezer ◽  
Ryan J. Post ◽  
David A. Bulkin ◽  
R. Becket Ebitz ◽  
Vladlena Lee ◽  
...  
Keyword(s):  
Ventral Tegmental Area ◽  
Neural Activity ◽  
Dopamine Neurons ◽  
Tonic Activity ◽  
Lateral Habenula ◽  
Negative Valence ◽  
Reward Seeking ◽  
Multiple Contexts ◽  
Seeking Behavior ◽  
Behavioral States

SUMMARYSurvival requires both the ability to persistently pursue goals and the ability to determine when it is time to stop, an adaptive balance of perseverance and disengagement. Neural activity in the lateral habenula (LHb) has been linked to aversion and negative valence, but its role in regulating the balance between reward-seeking and disengaged behavioral states remains unclear. Here, we show that LHb neural activity is tonically elevated during minutes-long disengagements from reward-seeking behavior, whether due to repeated reward omission or following sufficient consumption of reward. Further, we show that LHb inhibition extends ongoing reward-seeking behavioral states but does not prompt re-engagement. We find no evidence for similar tonic activity fluctuations in ventral tegmental area (VTA) dopamine neurons. Our findings implicate the LHb as a key mediator of disengagement from reward-seeking behavior in multiple contexts and argue against the idea that the LHb contributes to decisions solely by signaling aversion.

scholarly journals Functional evidence for a direct excitatory projection from the lateral habenula to the ventral tegmental area in the rat

2016 ◽  
Vol 116 (3) ◽  
pp. 1161-1174 ◽  
Author(s):  
P. Leon Brown ◽  
Paul D. Shepard
Keyword(s):  
Ventral Tegmental Area ◽  
Dopamine Neurons ◽  
Lateral Habenula ◽  
Aversive Stimuli ◽  
Rat Pups ◽  
Tegmental Nucleus ◽  
Fasciculus Retroflexus ◽  
Ventral Tegmental ◽  
Midbrain Dopamine ◽  
Midbrain Dopamine Neurons

The lateral habenula, a phylogenetically conserved epithalamic structure, is activated by aversive stimuli and reward omission. Excitatory efferents from the lateral habenula predominately inhibit midbrain dopamine neuronal firing through a disynaptic, feedforward inhibitory mechanism involving the rostromedial tegmental nucleus. However, the lateral habenula also directly targets dopamine neurons within the ventral tegmental area, suggesting that opposing actions may result from increased lateral habenula activity. In the present study, we tested the effect of habenular efferent stimulation on dopamine and nondopamine neurons in the ventral tegmental area of Sprague-Dawley rats using a parasagittal brain slice preparation. Single pulse stimulation of the fasciculus retroflexus excited 48% of dopamine neurons and 51% of nondopamine neurons in the ventral tegmental area of rat pups. These proportions were not altered by excision of the rostromedial tegmental nucleus and were evident in both cortical- and striatal-projecting dopamine neurons. Glutamate receptor antagonists blocked this excitation, and fasciculus retroflexus stimulation elicited evoked excitatory postsynaptic potentials with a nearly constant onset latency, indicative of a monosynaptic, glutamatergic connection. Comparison of responses in rat pups and young adults showed no significant difference in the proportion of neurons excited by fasciculus retroflexus stimulation. Our data indicate that the well-known, indirect inhibitory effect of lateral habenula activation on midbrain dopamine neurons is complemented by a significant, direct excitatory effect. This pathway may contribute to the role of midbrain dopamine neurons in processing aversive stimuli and salience.

scholarly journals Ventral tegmental area GABA neurons mediate stress-induced anhedonia

2020 ◽  
Author(s):  
Daniel C. Lowes ◽  
Linda A. Chamberlin ◽  
Lisa N. Kretsge ◽  
Emma S. Holt ◽  
Atheir I. Abbas ◽  
...  
Keyword(s):  
Ventral Tegmental Area ◽  
Low Frequency ◽  
Potential Mechanism ◽  
Gaba Neurons ◽  
Reward Seeking ◽  
Seeking Behavior ◽  
Stressful Experiences ◽  
Ventral Tegmental ◽  
Necessary And Sufficient ◽  
Depressive Episodes

AbstractStressful experiences frequently precede depressive episodes1. Depression results in anhedonia, or disrupted reward-seeking, in most patients2. In humans3,4 and rodents5,6, stress can disrupt reward-seeking, providing a potential mechanism by which stress can precipitate depression7-9. Yet despite decades investigating how stress modulates dopamine neuron transmission between the ventral tegmental area (VTA) and nucleus accumbens (NAc), the underpinnings of the stress-anhedonia transition remain elusive10-13. Here we show that during restraint stress, VTA GABA neurons drive low frequency NAc LFP oscillations, rhythmically modulating NAc firing rates. The strength of these stress-induced NAc oscillations predict the degree of impaired reward-seeking upon release from restraint. Inhibiting VTA GABA neurons disrupts stress-induced NAc oscillations and reverses the effect of stress on reward-seeking. By contrast, mimicking these oscillations with rhythmic VTA GABA stimulation in the absence of stress blunts subsequent reward-seeking. These experiments demonstrate that VTA GABA inputs to the NAc are both necessary and sufficient for stress-induced decreases in reward seeking behavior, elucidating a key circuit-level mechanism underlying stress-induced anhedonia.

scholarly journals Neurons in ventral tegmental area tonically inhibit sympathetic outflow to brown adipose tissue: possible mediation of thermogenic signals from lateral habenula

2019 ◽  
Vol 316 (1) ◽  
pp. R6-R12 ◽  
Author(s):  
Mariana Brizuela ◽  
Steven J. Swoap ◽  
James Ang ◽  
William W. Blessing ◽  
Youichirou Ootsuka
Keyword(s):  
Adipose Tissue ◽  
Brown Adipose Tissue ◽  
Ventral Tegmental Area ◽  
Dopamine Neurons ◽  
Lateral Habenula ◽  
Control Center ◽  
Brown Adipose ◽  
Medullary Raphe ◽  
Ventral Tegmental ◽  
Environmental Events

The lateral habenula (LHb), a nucleus involved in the response to salient, especially adverse, environmental events, is implicated in brown adipose tissue (BAT) thermogenesis caused by these events. LHb-elicited thermogenesis involves a neural pathway to the lower brain stem sympathetic control center in the medullary raphé. There are no direct connections from the LHb to the medullary raphé. LHb-mediated behavioral responses involve inhibitory control over the dopamine neurons in the ventral tegmental area (VTA), mediated via an excitatory drive from the LHb to GABAergic neurons in the tail of the VTA. We hypothesized that inhibition of the VTA is also involved in LHb-mediated BAT thermogenesis. To test this hypothesis, inhibition of neurons in the VTA with muscimol increased BAT sympathetic nerve discharge by 22.0 ± 9.2 dBμV ( n = 24, P < 0.0001) and BAT temperature by 1.2 ± 0.1°C ( P < 0.001). This response was abolished by inhibition of the medullary raphé neurons with muscimol. BAT thermogenesis initiated with focal injections of bicuculline in the LHb was reversed by subsequent blockade of GABAA receptors in the VTA with bicuculline. These results suggest that, at least in anesthetized rats, neurons in the VTA tonically inhibit BAT thermogenesis via a link, presently unknown, to the medullary raphé. Removal of this VTA-initiated inhibition is an important mechanism whereby LHb neurons activate BAT thermogenesis.

scholarly journals Ventral tegmental area GABA neurons mediate stress-induced blunted reward-seeking in mice

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Daniel C. Lowes ◽  
Linda A. Chamberlin ◽  
Lisa N. Kretsge ◽  
Emma S. Holt ◽  
Atheir I. Abbas ◽  
...  
Keyword(s):  
Ventral Tegmental Area ◽  
Neural Activity ◽  
Neural Encoding ◽  
Brain Areas ◽  
Gaba Neurons ◽  
Reward Seeking ◽  
Core Symptom ◽  
Stressful Experiences ◽  
Ventral Tegmental ◽  
Gabaergic Activity

AbstractDecreased pleasure-seeking (anhedonia) forms a core symptom of depression. Stressful experiences precipitate depression and disrupt reward-seeking, but it remains unclear how stress causes anhedonia. We recorded simultaneous neural activity across limbic brain areas as mice underwent stress and discovered a stress-induced 4 Hz oscillation in the nucleus accumbens (NAc) that predicts the degree of subsequent blunted reward-seeking. Surprisingly, while previous studies on blunted reward-seeking focused on dopamine (DA) transmission from the ventral tegmental area (VTA) to the NAc, we found that VTA GABA, but not DA, neurons mediate stress-induced blunted reward-seeking. Inhibiting VTA GABA neurons disrupts stress-induced NAc oscillations and rescues reward-seeking. By contrast, mimicking this signature of stress by stimulating NAc-projecting VTA GABA neurons at 4 Hz reproduces both oscillations and blunted reward-seeking. Finally, we find that stress disrupts VTA GABA, but not DA, neural encoding of reward anticipation. Thus, stress elicits VTA-NAc GABAergic activity that induces VTA GABA mediated blunted reward-seeking.

scholarly journals Evolution of circuits regulating pleasure and happiness with the habenula in control

CNS Spectrums ◽  
2017 ◽  
Vol 24 (02) ◽  
pp. 233-238 ◽  
Author(s):  
Anton J. M. Loonen ◽  
Svetlana A. Ivanova
Keyword(s):  
Globus Pallidus ◽  
Essential Role ◽  
Stress Disorders ◽  
Lateral Habenula ◽  
Glutamatergic Neurons ◽  
Nuclear Complex ◽  
Reward Seeking ◽  
Seeking Behavior ◽  
Neuroimaging Techniques

The habenula, which in humans is a small nuclear complex within the epithalamus, plays an essential role in regulating the intensity of reward-seeking and adversity-avoiding behavior in all vertebrate ancestors by regulating the activity of ascending midbrain monoaminergic tracts. In lampreys, considered to possess a brain comparable to humans’ earliest evolutionary vertebrate ancestor, the activity of the lateral habenula is controlled by a subset of glutamatergic neurons of the animal’s pallidum (habenula-projecting globus pallidus) that inhibit reward-seeking behavior when this conduct is not successful enough. The pathophysiological roles of the habenula and habenula-projecting globus pallidus in humans have hardly been studied, which is probably due to insufficient resolution of common neuroimaging techniques. Their dysregulation may, however, play an essential role in the pathogenesis of mood and stress disorders and addiction.

scholarly journals Repeated treatment with cocaine or methamphetamine increases CRF2 and decreases astrocytic markers in the ventral tegmental area and substantia nigra

2019 ◽  
Author(s):  
Amanda L. Sharpe ◽  
Marta Trzeciak ◽  
Phillip Douglas ◽  
Michael J. Beckstead
Keyword(s):  
Substantia Nigra ◽  
Ventral Tegmental Area ◽  
Glutamate Transporter ◽  
Dopamine Neurons ◽  
Repeated Treatment ◽  
Glial Glutamate Transporter ◽  
Seeking Behavior ◽  
Membrane Bound ◽  
Ventral Tegmental ◽  
Abused Drugs

AbstractDopamine neurons in the substantia nigra (SN) and ventral tegmental area (VTA) play a crucial role in the reinforcing properties of abused drugs including methamphetamine and cocaine. Evidence also suggests the involvement of non-dopaminergic transmitters, including glutamate and the stress-related peptide corticotropin-releasing factor (CRF), on the chronic effects of psychostimulants in the SN/VTA. Astrocytes express a variety of membrane-bound neurotransmitter receptors and transporters which influence neurotransmission in the SN/VTA. CRF2 activity in the VTA is important for stress-induced relapse and drug-seeking behavior, but the localization of its effects are not completely understood. Here we used immunofluorescence to identify the effect of methamphetamine and cocaine administration on astrocytes, the glial glutamate transporter GLAST, and CRF2 in the SN/VTA. We treated adult male mice with i.p. injections of methamphetamine (3 mg/kg), cocaine (10 mg/kg), or saline for 12 days. Coronal brain sections were processed for immunofluorescence using S100β (marker for astrocytes), glial-specific glutamate/aspartate transporters (GLAST), and CRF2. The results showed a significant decrease in GLAST immunofluorescence in brains of mice treated with cocaine or methamphetamine compared to saline. In addition, we observed increased labelling of CRF2 in drug treated groups, a decrease in the number of S100β positive cells, and an increase in co-staining of these two markers. Our results suggest that administration of either methamphetamine or cocaine decreases astrocytic markers and increases immunoreactivity for CRF2 in the VTA, an effect that is most pronounced in S100β positive cells.

scholarly journals Distinct neuronal subtypes of the lateral habenula differentially target ventral tegmental area dopamine neurons

2019 ◽  
Author(s):  
Michael L. Wallace ◽  
Kee Wui Huang ◽  
Daniel Hochbaum ◽  
Minsuk Hyun ◽  
Gianna Radeljic ◽  
...  
Keyword(s):  
Ventral Tegmental Area ◽  
Molecular Diversity ◽  
Transcriptional Profiling ◽  
Retrograde Tracing ◽  
Dopamine Neurons ◽  
Lateral Habenula ◽  
Subtype Specificity ◽  
Medial Habenula ◽  
Neuronal Subtype ◽  
Ventral Tegmental

ABSTRACTThe lateral habenula (LHb) is an epithalamic brain structure critical for processing and adapting to negative action outcomes. However, despite the importance of LHb to behavior and the clear anatomical and molecular diversity of LHb neurons, the neuron types of the habenula remain unknown. Here we use high-throughput single-cell transcriptional profiling, monosynaptic retrograde tracing, and multiplexed FISH to characterize the cells of the mouse habenula. We find 5 subtypes of neurons in the medial habenula (MHb) that are organized into anatomical subregions. In the LHb we describe 4 neuronal subtypes and show that they differentially target dopaminergic and GABAergic cells in the ventral tegmental area (VTA). These data provide a valuable resource for future study of habenular function and dysfunction and demonstrate neuronal subtype specificity in the LHb-VTA circuit.

scholarly journals Optogenetic stimulation of lateral hypothalamic orexin/dynorphin inputs in the ventral tegmental area potentiates mesolimbic dopamine neurotransmission and promotes reward-seeking behaviours

2021 ◽  
Author(s):  
Catherine S. Thomas ◽  
Aida Mohammadkhani ◽  
Madiha Rana ◽  
Min Qiao ◽  
Corey Baimel ◽  
...  
Keyword(s):  
Ventral Tegmental Area ◽  
Real Time ◽  
Place Preference ◽  
Dopamine Neurons ◽  
Mesolimbic Dopamine ◽  
Optical Stimulation ◽  
Lateral Hypothalamic ◽  
Reward Seeking ◽  
Ventral Tegmental ◽  
Stimulation Of

AbstractReward and reinforcement processes are critical for survival and propagation of genes. While numerous brain systems underlie these processes, a cardinal role is ascribed to mesolimbic dopamine. However, ventral tegmental area (VTA) dopamine neurons receive complex innervation and various neuromodulatory factors, including input from lateral hypothalamic (LH) orexin/hypocretin neurons which also express and co-release the neuropeptide, dynorphin. Dynorphin in the VTA induces aversive conditioning through the Kappa opioid receptor (KOR) and decreases dopamine when administered intra-VTA. Exogenous application of orexin or orexin 1 receptor (oxR1) antagonists in the VTA bidirectionally modulates dopamine-driven motivation and reward-seeking behaviours, including the attribution of motivational value to primary rewards and associated conditioned stimuli. However, the effect of endogenous stimulation of LH orexin/dynorphin-containing projections to the VTA and the potential contribution of co-released dynorphin on mesolimbic dopamine and reward related processes remains uncharacterised. We combined optogenetic, electrochemical, and behavioural approaches to examine this. We found that optical stimulation of LH orexin/dynorphin inputs in the VTA potentiates mesolimbic dopamine neurotransmission in the nucleus accumbens (NAc) core, produces real time and conditioned place preference, and increases the food cue-directed orientation in a Pavlovian conditioning procedure. LH orexin/dynorphin potentiation of NAc dopamine release and real time place preference was blocked by an oxR1, but not KOR antagonist. Thus, rewarding effects associated with optical stimulation of LH orexin/dynorphin inputs in the VTA are predominantly driven by orexin rather than dynorphin.

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