Entopeduncular nucleus projections to the lateral habenula contribute to cocaine avoidance

✓ The effect of fetal mesencephalic implants on glucose utilization in selected brain structures and on apomorphine-induced rotational behavior was measured in rats with a unilateral lesion of the substantia nigra. Ipsilateral, but not contralateral, implants decreased the rotational behavior induced by apomorphine. In addition, the nigral lesion decreased glucose utilization in the dorso- and ventrolateral quadrants of the striatum and in the entopeduncular nucleus but increased glucose utilization in the ipsilateral globus pallidus and lateral habenula. The increased metabolism in the globus pallidus was attenuated by ipsilateral, but not contralateral, mesencephalic implants which also decreased glucose utilization in the dorsomedial caudate nucleus. These results indicate that the ability of an ipsilateral mesencephalic graft to ameliorate the motor behavior in rats with nigral lesions is associated with changes in the functional activity of the ipsilateral globus pallidus.

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Biophysical demonstration of co-packaging of glutamate and GABA in individual synaptic vesicles in the central nervous system

10.1101/2021.03.23.436594 ◽

2021 ◽

Author(s):

SeulAh Kim ◽

Michael Wallace ◽

Mahmoud El-Rifai ◽

Alexa Knudsen ◽

Bernardo Sabatini

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Computational Modeling ◽

Synaptic Vesicles ◽

Entopeduncular Nucleus ◽

Lateral Habenula ◽

Ionotropic Receptors ◽

The Central Nervous System ◽

Novel Method ◽

The Brain

Many mammalian neurons release multiple neurotransmitters to activate diverse classes of ionotropic receptors on their postsynaptic targets. Entopeduncular nucleus somatostatin (EP Sst+) neurons that project to the lateral habenula (LHb) release both glutamate and GABA, but it is unclear if these are packaged into the same or segregated pools of synaptic vesicles. Here we describe a novel method combining electrophysiology, spatially-patterned optogenetics, and computational modeling designed to analyze the mechanism of glutamate/GABA corelease. We find that the properties of PSCs elicited in LHb neurons by optogenetic activation of EP Sst+ terminals are only consistent with co-packaging of glutamate and GABA into individual vesicles. Furthermore, serotonin, which acts presynaptically to weaken EP Sst+ to LHb synapses, does so by altering the release probability of vesicles containing both transmitters. Our approach is broadly applicable to the study of multi-transmitter neurons throughout the brain and our results constrain mechanisms of neuromodulation in LHb.

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Cocaine withdrawal reduces GABA B R transmission at entopeduncular nucleus – lateral habenula synapses

European Journal of Neuroscience ◽

10.1111/ejn.14120 ◽

2018 ◽

Vol 50 (3) ◽

pp. 2124-2133 ◽

Cited By ~ 5

Author(s):

Dorine Tan ◽

Alvaro Nuno‐Perez ◽

Manuel Mameli ◽

Frank J. Meye

Keyword(s):

Entopeduncular Nucleus ◽

Cocaine Withdrawal ◽

Lateral Habenula

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The entopeduncular nucleus drives lateral habenula responses to negative but not positive or neutral affective stimuli

10.1101/408963 ◽

2018 ◽

Author(s):

Hao Li ◽

Dominika Pullmann ◽

Thomas C. Jhou

Keyword(s):

Burst Firing ◽

Entopeduncular Nucleus ◽

Lateral Habenula ◽

Affective Stimuli ◽

Tegmental Nucleus ◽

Rostromedial Tegmental Nucleus

AbstractLateral habenula (LHb) neurons are activated by negative motivational stimuli and play key roles in the pathophysiology of depression. Early reports indicated the possibility that rostral entopeduncular nucleus (rEPN) neurons drive these LHb responses, but this influence remains untested. We find that both rEPN and LHb neurons in rats exhibit similar activation/inhibition patterns after negative/positive motivational stimuli, but that the rEPN influence on LHb firing is surprisingly selective. Temporary rEPN inactivation decreases LHb basal and burst firing, and eliminates LHb responses to footshock-predictive cues occurring 40-100ms but not 10-30ms post-stimulus, nor on responses to positive/neutral motivational stimuli. Additionally, rEPN inactivation partially but not fully reduces LHb responses to signaled footshocks, while excitotoxic rEPN lesions only partially diminish footshock-induced cFos in the LHb and its rostromedial tegmental nucleus targets. Together, our findings indicate an important but selective role of the rEPN in driving LHb responses to motivational stimuli.

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The habenula-targeting neurons in the mouse entopeduncular nucleus contain not only somatostatin-positive neurons but also nitric oxide synthase-positive neurons

Brain Structure and Function ◽

10.1007/s00429-021-02264-1 ◽

2021 ◽

Author(s):

Yuta Miyamoto ◽

Takaichi Fukuda

Keyword(s):

Nitric Oxide ◽

Basal Ganglia ◽

Nitric Oxide Synthase ◽

Core Region ◽

Entopeduncular Nucleus ◽

Double Positive ◽

Lateral Habenula ◽

Aversive Stimuli ◽

Oxide Synthase ◽

Shell Region

AbstractThe entopeduncular nucleus (EPN) in rodents is one of the two major output nuclei of the basal ganglia and corresponds to the internal segment of the globus pallidus in primates. Previous studies have shown that the EPN contains three types of neurons that project to different targets, namely, parvalbumin (PV)-, somatostatin (SOM)-, and choline acetyltransferase-positive neurons. However, we have recently reported that neurons lacking immunoreactivities for these substances are present in the EPN. Here, we demonstrate that 27.7% of all EPN neurons showed immunoreactivity for nitric oxide synthase (NOS). Among them, NOS-only positive and NOS/SOM double-positive neurons accounted for 20.1% and 6.8%, respectively, whereas NOS/PV double-positive neurons were rarely observed. NOS-containing neurons were distributed in a shell region surrounding the thalamus-targeting, PV-rich core region of the EPN, especially in the ventromedial part of the shell. The retrograde tracer fluoro-gold (FG) was injected into several target regions of EPN neurons. Among FG-labeled EPN neurons after injection into the lateral habenula (LHb), NOS-only positive, NOS/SOM double-positive, and SOM-only positive neurons accounted for 25.7%, 15.2%, and 59.1%, respectively. We conclude that NOS-positive neurons are the second major population of LHb-targeting EPN neurons, suggesting their possible involvement in behaviors in response to aversive stimuli.

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Valence-encoding in the lateral habenula arises from the entopeduncular region

eLife ◽

10.7554/elife.41223 ◽

2019 ◽

Vol 8 ◽

Cited By ~ 8

Author(s):

Hao Li ◽

Dominika Pullmann ◽

Thomas C Jhou

Keyword(s):

Burst Firing ◽

Entopeduncular Nucleus ◽

In Vivo Electrophysiology ◽

Lateral Habenula ◽

Tegmental Nucleus ◽

Rostromedial Tegmental Nucleus

Lateral habenula (LHb) neurons are activated by negative motivational stimuli and play key roles in the pathophysiology of depression. Prior reports suggested that rostral entopeduncular nucleus (rEPN) neurons drive these responses in the LHb and rostromedial tegmental nucleus (RMTg), but these influences remain untested. Using rabies viral tracers, we demonstrate disynaptic projections from the rEPN to RMTg, but not VTA, via the LHb in rats. Using in vivo electrophysiology, we find that rEPN or LHb subpopulations exhibit activation/inhibition patterns after negative/positive motivational stimuli, similar to the RMTg, while temporary inactivation of a region centered on the rEPN decreases LHb basal and burst firing, and reduces valence-related signals in LHb neurons. Additionally, excitotoxic rEPN lesions partly diminish footshock-induced cFos in the LHb and RMTg. Together, our findings indicate an important role of the rEPN, and possibly immediately adjacent hypothalamus, in driving basal activities and valence processing in LHb and RMTg neurons.

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