Midbrain dopaminergic innervation of the hippocampus is sufficient to modulate formation of aversive memories

2021 ◽  
Vol 118 (40) ◽  
pp. e2111069118
Author(s):  
Theodoros Tsetsenis ◽  
Julia K. Badyna ◽  
Julianne A. Wilson ◽  
Xiaowen Zhang ◽  
Elizabeth N. Krizman ◽  
...  
Keyword(s):  
Dopaminergic Neurons ◽  
Dorsal Hippocampus ◽  
Memory Formation ◽  
Dopamine Neurons ◽  
Substantia Nigra Pars Compacta ◽  
Aversive Learning ◽  
Contextual Fear ◽  
Dopaminergic Transmission ◽  
Midbrain Dopaminergic Neurons ◽  
Midbrain Dopamine

Aversive memories are important for survival, and dopaminergic signaling in the hippocampus has been implicated in aversive learning. However, the source and mode of action of hippocampal dopamine remain controversial. Here, we utilize anterograde and retrograde viral tracing methods to label midbrain dopaminergic projections to the dorsal hippocampus. We identify a population of midbrain dopaminergic neurons near the border of the substantia nigra pars compacta and the lateral ventral tegmental area that sends direct projections to the dorsal hippocampus. Using optogenetic manipulations and mutant mice to control dopamine transmission in the hippocampus, we show that midbrain dopamine potently modulates aversive memory formation during encoding of contextual fear. Moreover, we demonstrate that dopaminergic transmission in the dorsal CA1 is required for the acquisition of contextual fear memories, and that this acquisition is sustained in the absence of catecholamine release from noradrenergic terminals. Our findings identify a cluster of midbrain dopamine neurons that innervate the hippocampus and show that the midbrain dopamine neuromodulation in the dorsal hippocampus is sufficient to maintain aversive memory formation.

scholarly journals Involvement of the Protein Ras Homolog Enriched in the Striatum, Rhes, in Dopaminergic Neurons Degeneration: Link to Parkison’s Disease

2021 ◽  
Author(s):  
Marcello Serra ◽  
Annalisa Pinna ◽  
Giulia Costa ◽  
Alessandro Usiello ◽  
Massimo Pasqualetti ◽  
...  
Keyword(s):  
Dopaminergic Neurons ◽  
Dorsal Striatum ◽  
Substantia Nigra Pars Compacta ◽  
Nigrostriatal System ◽  
Mrna Levels ◽  
Dopaminergic Transmission ◽  
A2a Receptors ◽  
Midbrain Dopaminergic Neurons ◽  
Pka Pathway ◽  
Adenosine A2a

Rhes is one of the most interesting proteins regulated by thyroid hormones that, through the inhibition of the striatal cAMP/PKA pathway, acts as a modulator of dopamine neurotransmission. It is expressed at high levels in the dorsal striatum, with a medial-to-lateral expression gradient reflecting that of both dopamine D2 and adenosine A2A receptors. Rhes is also present in the hippocampus, cerebral cortex, olfactory tubercle and bulb, substantia nigra pars compacta (SNc) and ventral tegmental area of the rodent brain. In line with Rhes-dependent regulation of dopaminergic transmission, several data showed that lack of Rhes enhanced cocaine and amphetamine-induced motor stimulation in mice. Previous studies showed that pharmacological depletion of dopamine significantly reduces Rhes mRNA levels in rodents, non-human primates and Parkinson’s disease (PD) patients, suggesting a link between dopaminergic innervation and physiological Rhes mRNA expression. Rhes protein binds to and activates striatal mTORC1, and modulates L-DOPA-induced dyskinesia in PD rodent models. Finally, Rhes is involved in the survival of mouse midbrain dopaminergic neurons of SNc, thus pointing towards a Rhes-dependent modulation of autophagy and mitophagy processes, and encouraging further investigations about mechanisms underlying dysfunctions of the nigrostriatal system.

scholarly journals Involvement of the Protein Ras Homolog Enriched in the Striatum, Rhes, in Dopaminergic Neurons’ Degeneration: Link to Parkinson’s Disease

2021 ◽  
Vol 22 (10) ◽  
pp. 5326
Author(s):  
Marcello Serra ◽  
Annalisa Pinna ◽  
Giulia Costa ◽  
Alessandro Usiello ◽  
Massimo Pasqualetti ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Dopaminergic Neurons ◽  
Dorsal Striatum ◽  
Substantia Nigra Pars Compacta ◽  
Nigrostriatal System ◽  
Mrna Levels ◽  
Dopaminergic Transmission ◽  
A2a Receptors ◽  
Midbrain Dopaminergic Neurons

Rhes is one of the most interesting genes regulated by thyroid hormones that, through the inhibition of the striatal cAMP/PKA pathway, acts as a modulator of dopamine neurotransmission. Rhes mRNA is expressed at high levels in the dorsal striatum, with a medial-to-lateral expression gradient reflecting that of both dopamine D2 and adenosine A2A receptors. Rhes transcript is also present in the hippocampus, cerebral cortex, olfactory tubercle and bulb, substantia nigra pars compacta (SNc) and ventral tegmental area of the rodent brain. In line with Rhes-dependent regulation of dopaminergic transmission, data showed that lack of Rhes enhanced cocaine- and amphetamine-induced motor stimulation in mice. Previous studies showed that pharmacological depletion of dopamine significantly reduces Rhes mRNA levels in rodents, non-human primates and Parkinson’s disease (PD) patients, suggesting a link between dopaminergic innervation and physiological Rhes mRNA expression. Rhes protein binds to and activates striatal mTORC1, and modulates L-DOPA-induced dyskinesia in PD rodent models. Finally, Rhes is involved in the survival of mouse midbrain dopaminergic neurons of SNc, thus pointing towards a Rhes-dependent modulation of autophagy and mitophagy processes, and encouraging further investigations about mechanisms underlying dysfunctions of the nigrostriatal system.

scholarly journals Aldehyde dehydrogenase 1a1 mediates a GABA synthesis pathway in midbrain dopaminergic neurons

Science ◽  
2015 ◽  
Vol 350 (6256) ◽  
pp. 102-106 ◽  
Author(s):  
Jae-Ick Kim ◽  
Subhashree Ganesan ◽  
Sarah X. Luo ◽  
Yu-Wei Wu ◽  
Esther Park ◽  
...  
Keyword(s):  
Aldehyde Dehydrogenase ◽  
Dopaminergic Neurons ◽  
Dopamine Neurons ◽  
Inhibitory Neurotransmitter ◽  
Midbrain Dopaminergic Neurons ◽  
Evolutionarily Conserved ◽  
Gaba Synthesis ◽  
Midbrain Dopamine ◽  
Midbrain Dopamine Neurons

Midbrain dopamine neurons are an essential component of the basal ganglia circuitry, playing key roles in the control of fine movement and reward. Recently, it has been demonstrated that γ-aminobutyric acid (GABA), the chief inhibitory neurotransmitter, is co-released by dopamine neurons. Here, we show that GABA co-release in dopamine neurons does not use the conventional GABA-synthesizing enzymes, glutamate decarboxylases GAD65 and GAD67. Our experiments reveal an evolutionarily conserved GABA synthesis pathway mediated by aldehyde dehydrogenase 1a1 (ALDH1a1). Moreover, GABA co-release is modulated by ethanol (EtOH) at concentrations seen in blood alcohol after binge drinking, and diminished ALDH1a1 leads to enhanced alcohol consumption and preference. These findings provide insights into the functional role of GABA co-release in midbrain dopamine neurons, which may be essential for reward-based behavior and addiction.

scholarly journals Electrical and Ca2+ signaling in dendritic spines of substantia nigra dopaminergic neurons

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Travis A Hage ◽  
Yujie Sun ◽  
Zayd M Khaliq
Keyword(s):  
Dendritic Spines ◽  
Dopaminergic Neurons ◽  
Fluorescence Recovery After Photobleaching ◽  
Dopamine Neurons ◽  
Fixed Tissue ◽  
Spine Length ◽  
Relative Contribution ◽  
Midbrain Dopamine ◽  
Shaft Synapses ◽  
And Function

Little is known about the density and function of dendritic spines on midbrain dopamine neurons, or the relative contribution of spine and shaft synapses to excitability. Using Ca2+ imaging, glutamate uncaging, fluorescence recovery after photobleaching and transgenic mice expressing labeled PSD-95, we comparatively analyzed electrical and Ca2+ signaling in spines and shaft synapses of dopamine neurons. Dendritic spines were present on dopaminergic neurons at low densities in live and fixed tissue. Uncaging-evoked potential amplitudes correlated inversely with spine length but positively with the presence of PSD-95. Spine Ca2+ signals were less sensitive to hyperpolarization than shaft synapses, suggesting amplification of spine head voltages. Lastly, activating spines during pacemaking, we observed an unexpected enhancement of spine Ca2+ midway throughout the spike cycle, likely involving recruitment of NMDA receptors and voltage-gated conductances. These results demonstrate functionality of spines in dopamine neurons and reveal a novel modulation of spine Ca2+ signaling during pacemaking.

Differential Modulation by Nicotine of Substantia Nigra Versus Ventral Tegmental Area Dopamine Neurons

2007 ◽  
Vol 98 (6) ◽  
pp. 3388-3396 ◽  
Author(s):  
J. Russel Keath ◽  
Michael P. Iacoviello ◽  
Lindy E. Barrett ◽  
Huibert D. Mansvelder ◽  
Daniel S. McGehee
Keyword(s):  
Substantia Nigra ◽  
Ventral Tegmental Area ◽  
Dorsal Striatum ◽  
Dopamine Neurons ◽  
Substantia Nigra Pars Compacta ◽  
Synaptic Modulation ◽  
Afferent Projections ◽  
Ventral Tegmental ◽  
Midbrain Dopamine ◽  
Da Release

Midbrain dopamine (DA) neurons are found in two nuclei, the substantia nigra pars compacta (SNc) and ventral tegmental area (VTA). The SNc dopaminergic projections to the dorsal striatum are involved in voluntary movement and habit learning, whereas the VTA projections to the ventral striatum contribute to reward and motivation. Nicotine induces profound DA release from VTA dopamine neurons but substantially less from the SNc. Nicotinic acetylcholine receptor (nAChR) expression differs between these nuclei, but it is unknown whether there are differences in nAChR expression on the afferent projections to these nuclei. Here we have compared the nicotinic modulation of excitatory and inhibitory synaptic inputs to VTA and SNc dopamine neurons. Although nicotine enhances both the excitatory and inhibitory drive to SNc DA cells with response magnitudes similar to those seen in the VTA, the prevalence of these responses in SNc is much lower. We also found that a mixture of nAChR subtypes underlies the synaptic modulation in SNc, further distinguishing this nucleus from the VTA, where α7 nAChRs enhance glutamate inputs and non-α7 receptors enhance GABA inputs. Finally, we compared the nicotine sensitivity of DA neurons in these two nuclei and found larger response magnitudes in VTA relative to SNc. Thus the observed differences in nicotine-induced DA release from VTA and SNc are likely due to differences in nAChR expression on the afferent inputs as well as on the DA neurons themselves. This may explain why nicotine has a greater effect on behaviors associated with the VTA than the SNc.

scholarly journals AMPK Signaling in the Dorsal Hippocampus Negatively Regulates Contextual Fear Memory Formation

2015 ◽  
Vol 41 (7) ◽  
pp. 1849-1864 ◽  
Author(s):  
Ying Han ◽  
Yixiao Luo ◽  
Jia Sun ◽  
Zengbo Ding ◽  
Jianfeng Liu ◽  
...  
Keyword(s):  
Dorsal Hippocampus ◽  
Fear Memory ◽  
Memory Formation ◽  
Contextual Fear ◽  
Ampk Signaling ◽  
Contextual Fear Memory

scholarly journals Spatial RNA Sequencing Identifies Robust Markers of Vulnerable and Resistant Human Midbrain Dopamine Neurons and Their Expression in Parkinson’s Disease

2021 ◽  
Vol 14 ◽  
Author(s):  
Julio Aguila ◽  
Shangli Cheng ◽  
Nigel Kee ◽  
Ming Cao ◽  
Menghan Wang ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Small Sample ◽  
Dopamine Neurons ◽  
Substantia Nigra Pars Compacta ◽  
Minimal Sample ◽  
Differential Vulnerability ◽  
Minimal Sample Size ◽  
Midbrain Dopamine ◽  
Small Sample Sizes

Defining transcriptional profiles of substantia nigra pars compacta (SNc) and ventral tegmental area (VTA) dopamine neurons is critical to understanding their differential vulnerability in Parkinson’s Disease (PD). Here, we determine transcriptomes of human SNc and VTA dopamine neurons using LCM-seq on a large sample cohort. We apply a bootstrapping strategy as sample input to DESeq2 and identify 33 stably differentially expressed genes (DEGs) between these two subpopulations. We also compute a minimal sample size for identification of stable DEGs, which highlights why previous reported profiles from small sample sizes display extensive variability. Network analysis reveal gene interactions unique to each subpopulation and highlight differences in regulation of mitochondrial stability, apoptosis, neuronal survival, cytoskeleton regulation, extracellular matrix modulation as well as synapse integrity, which could explain the relative resilience of VTA dopamine neurons. Analysis of PD tissues showed that while identified stable DEGs can distinguish the subpopulations also in disease, the SNc markers SLIT1 and ATP2A3 were down-regulated and thus appears to be biomarkers of disease. In summary, our study identifies human SNc and VTA marker profiles, which will be instrumental for studies aiming to modulate dopamine neuron resilience and to validate cell identity of stem cell-derived dopamine neurons.

scholarly journals Dopamine synapse is a neuroligin-2–mediated contact between dopaminergic presynaptic and GABAergic postsynaptic structures

2016 ◽  
Vol 113 (15) ◽  
pp. 4206-4211 ◽  
Author(s):  
Motokazu Uchigashima ◽  
Toshihisa Ohtsuka ◽  
Kazuto Kobayashi ◽  
Masahiko Watanabe
Keyword(s):  
Dopamine Receptors ◽  
Synapse Formation ◽  
Detection Threshold ◽  
Dopamine Neurons ◽  
Dopamine Synthesis ◽  
Dopaminergic Transmission ◽  
Gabaergic Synapses ◽  
Midbrain Dopamine ◽  
Mediated Contact ◽  
Midbrain Dopamine Neurons

Midbrain dopamine neurons project densely to the striatum and form so-called dopamine synapses on medium spiny neurons (MSNs), principal neurons in the striatum. Because dopamine receptors are widely expressed away from dopamine synapses, it remains unclear how dopamine synapses are involved in dopaminergic transmission. Here we demonstrate that dopamine synapses are contacts formed between dopaminergic presynaptic and GABAergic postsynaptic structures. The presynaptic structure expressed tyrosine hydroxylase, vesicular monoamine transporter-2, and plasmalemmal dopamine transporter, which are essential for dopamine synthesis, vesicular filling, and recycling, but was below the detection threshold for molecules involving GABA synthesis and vesicular filling or for GABA itself. In contrast, the postsynaptic structure of dopamine synapses expressed GABAergic molecules, including postsynaptic adhesion molecule neuroligin-2, postsynaptic scaffolding molecule gephyrin, and GABAA receptor α1, without any specific clustering of dopamine receptors. Of these, neuroligin-2 promoted presynaptic differentiation in axons of midbrain dopamine neurons and striatal GABAergic neurons in culture. After neuroligin-2 knockdown in the striatum, a significant decrease of dopamine synapses coupled with a reciprocal increase of GABAergic synapses was observed on MSN dendrites. This finding suggests that neuroligin-2 controls striatal synapse formation by giving competitive advantage to heterologous dopamine synapses over conventional GABAergic synapses. Considering that MSN dendrites are preferential targets of dopamine synapses and express high levels of dopamine receptors, dopamine synapse formation may serve to increase the specificity and potency of dopaminergic modulation of striatal outputs by anchoring dopamine release sites to dopamine-sensing targets.

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