Synaptic structure and connectivity of serotonin terminals in the ventral tegmental area: potential sites for modulation of mesolimbic dopamine neurons

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 orexin/hypocretin neurons which also express and co-release the neuropeptide, dynorphin (LHox/dyn). 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 LHox/dyn-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 LHox/dyn inputs in the VTA potentiates mesolimbic dopamine neurotransmission in the nucleus accumbens (NAc) core, produces real time and place preference, and increases the incentive value attributed to a Pavlovian food cue. LHox/dyn potentiation of NAc dopamine release and real time place preference was completely blocked by an OXR1 antagonist. Thus, rewarding effects associated with optical stimulation of LHox/dyn inputs in the VTA are predominantly driven by orexin rather than dynorphin.

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

Neuropsychopharmacology ◽

10.1038/s41386-021-01196-y ◽

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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Injections of 6-hydroxydopamine into the ventral tegmental area destroy mesolimbic dopamine neurons but spare the locomotor activating effects of nicotine in the rat

Neuroscience Letters ◽

10.1016/0304-3940(94)90428-6 ◽

1994 ◽

Vol 168 (1-2) ◽

pp. 111-114 ◽

Cited By ~ 22

Author(s):

P. Vezina ◽

D. Hervé ◽

J. Glowinski ◽

J.P. Tassin

Keyword(s):

Ventral Tegmental Area ◽

Dopamine Neurons ◽

Mesolimbic Dopamine ◽

Ventral Tegmental ◽

6 Hydroxydopamine

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Faculty Opinions recommendation of Uniform inhibition of dopamine neurons in the ventral tegmental area by aversive stimuli.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1018433.208502 ◽

2004 ◽

Author(s):

Edvard I Moser

Keyword(s):

Ventral Tegmental Area ◽

Dopamine Neurons ◽

Aversive Stimuli ◽

Ventral Tegmental

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Faculty Opinions recommendation of Optogenetic activation of dopamine neurons in the ventral tegmental area induces reanimation from general anesthesia.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.726897366.793525487 ◽

2016 ◽

Author(s):

Stan Leung ◽

Tao Luo

Keyword(s):

General Anesthesia ◽

Ventral Tegmental Area ◽

Dopamine Neurons ◽

Ventral Tegmental

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Supramammillary neurons projecting to the septum regulate dopamine and motivation for environmental interaction in mice

Nature Communications ◽

10.1038/s41467-021-23040-z ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Andrew J. Kesner ◽

Rick Shin ◽

Coleman B. Calva ◽

Reuben F. Don ◽

Sue Junn ◽

...

Keyword(s):

Ventral Tegmental Area ◽

Dopamine Neurons ◽

Theta Oscillations ◽

Mesolimbic Dopamine ◽

Sucrose Consumption ◽

Behavioral Interaction ◽

Hypothalamic Structure ◽

Hippocampal Theta ◽

Substances Of Abuse ◽

Stimulation Of

AbstractThe supramammillary region (SuM) is a posterior hypothalamic structure, known to regulate hippocampal theta oscillations and arousal. However, recent studies reported that the stimulation of SuM neurons with neuroactive chemicals, including substances of abuse, is reinforcing. We conducted experiments to elucidate how SuM neurons mediate such effects. Using optogenetics, we found that the excitation of SuM glutamatergic (GLU) neurons was reinforcing in mice; this effect was relayed by their projections to septal GLU neurons. SuM neurons were active during exploration and approach behavior and diminished activity during sucrose consumption. Consistently, inhibition of SuM neurons disrupted approach responses, but not sucrose consumption. Such functions are similar to those of mesolimbic dopamine neurons. Indeed, the stimulation of SuM-to-septum GLU neurons and septum-to-ventral tegmental area (VTA) GLU neurons activated mesolimbic dopamine neurons. We propose that the supramammillo-septo-VTA pathway regulates arousal that reinforces and energizes behavioral interaction with the environment.

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