Differential Control of Dopaminergic Excitability and Locomotion by Cholinergic Inputs in Mouse Substantia Nigra

Estakhr, Jasem; Abazari, Danya; Frisby, Kaitlyn; McIntosh, J. Michael; Nashmi, Raad

doi:10.1016/j.cub.2017.05.084

Cited by 31 publications

(28 citation statements)

References 36 publications

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“…DA neurons within the VTA and SN are molecularly, anatomically and functionally heterogeneous 38 . Two populations of DA neurons, corresponding to medial-SN and lateral-SN, have been recently identified based on molecular as well as electrophysiological characteristics 39 , 40 . We therefore, distinguished between medial and lateral recordings obtained from SN (SNM, n = 5 and SNL, n = 6 respectively).…”

Section: Resultsmentioning

confidence: 99%

Circadian and Homeostatic Modulation of Multi-Unit Activity in Midbrain Dopaminergic Structures

Fifel

Meijer

Deboer

2018

Sci Rep

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Although the link between sleep disturbances and dopamine (DA)-related neurological and neuropsychiatric disorders is well established, the impact of sleep alterations on neuronal activity of midbrain DA-ergic structures is currently unknown. Here, using wildtype C57Bl mice, we investigated the circadian- and sleep-related modulation of electrical neuronal activity in midbrain ventral-tegmental-area (VTA) and substantia nigra (SN). We found no significant circadian modulation of activity in SN while VTA displayed a low amplitude but significant circadian modulation with increased firing rates during the active phase. Combining neural activity recordings with electroencephalogram (EEG) recordings revealed a strong vigilance state dependent modulation of neuronal activity with increased activity during wakefulness and rapid eye movement sleep relative to non-rapid eye movement sleep in both SN and VTA. Six-hours of sleep deprivation induced a significant depression of neuronal activity in both areas. Surprisingly, these alterations lasted for up to 48 hours and persisted even after the normalization of cortical EEG waves. Our results show that sleep and sleep disturbances significantly affect neuronal activity in midbrain DA structures. We propose that these changes in neuronal activity underlie the well-known relationship between sleep alterations and several disorders involving dysfunction of the DA circuitry such as addiction and depression.

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Section: Resultsmentioning

confidence: 99%

Circadian and Homeostatic Modulation of Multi-Unit Activity in Midbrain Dopaminergic Structures

Fifel

Meijer

Deboer

2018

Sci Rep

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“…At cellular level, the glutamate concentration is affected by differential expression of glutamatergic and neuropeptide receptors. Additionally, extensive arboreal structures can tend to hyperexcitation of glutamate receptors even at the physiological levels of glutamate concentration (Pahapill and Lozano, 2000;Heng et al, 2009;Pacelli et al, 2015;Estakhr et al, 2017;Wang and Reddy, 2017;Giguère et al, 2019;Gregory et al, 2019). Finally, at systems level, overexcitation from pathogenic nuclei can lead to calcium accumulation in ER and mitochondria, which in turn results in neurodegeneration (Rodriguez et al, 1998;Hansson et al, 1999;Pahapill and Lozano, 2000;Kawahara et al, 2003;Vaarmann et al, 2013;Muddapu et al, 2019).…”

Section: How Do Glutamate Toxicity and Calcium Load Affect Mitochondrmentioning

confidence: 99%

Neurodegenerative Diseases – Is Metabolic Deficiency the Root Cause?

et al. 2020

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Neurodegenerative diseases, including Alzheimer, Parkinson, Huntington, and amyotrophic lateral sclerosis, are a prominent class of neurological diseases currently without a cure. They are characterized by an inexorable loss of a specific type of neurons. The selective vulnerability of specific neuronal clusters (typically a subcortical cluster) in the early stages, followed by the spread of the disease to higher cortical areas, is a typical pattern of disease progression. Neurodegenerative diseases share a range of molecular and cellular pathologies, including protein aggregation, mitochondrial dysfunction, glutamate toxicity, calcium load, proteolytic stress, oxidative stress, neuroinflammation, and aging, which contribute to neuronal death. Efforts to treat these diseases are often limited by the fact that they tend to address any one of the above pathological changes while ignoring others. Lack of clarity regarding a possible root cause that underlies all the above pathologies poses a significant challenge. In search of an integrative theory for neurodegenerative pathology, we hypothesize that metabolic deficiency in certain vulnerable neuronal clusters is the common underlying thread that links many dimensions of the disease. The current review aims to present an outline of such an integrative theory. We present a new perspective of neurodegenerative diseases as metabolic disorders at molecular, cellular, and systems levels. This helps to understand a common underlying mechanism of the many facets of the disease and may lead to more promising disease-modifying therapeutic interventions. Here, we briefly discuss the selective metabolic vulnerability of specific neuronal clusters and also the involvement of glia and vascular dysfunctions. Any failure in satisfaction of the metabolic demand by the neurons triggers a chain of events that precipitate various manifestations of neurodegenerative pathology.

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“…SNc DA cells represent an important output target of PPN ACh neurons (Woolf and Butcher, 1986 ; Beninato and Spencer, 1987 , 1988 ). A certain degree of heterogeneity has been reported; specifically, the projection onto the lateral SNc DA neurons is mainly excitatory (nicotinic or glutamatergic) and promotes locomotion whereas the medial SNc DA neurons receive mostly cholinergic mediated GABAergic transmission, which inhibits motor activity (Estakhr et al, 2017 ).…”

Section: Introductionmentioning

confidence: 99%

Dopamine and Acetylcholine, a Circuit Point of View in Parkinson’s Disease

Rizzi

Tan

2017

Front. Neural Circuits

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Data from the World Health Organization (National Institute on Aging, 2011) and the National Institutes of Health (He et al., 2016) predicts that while today the worldwide population over 65 years of age is estimated around 8.5%, this number will reach an astounding 17% by 2050. In this framework, solving current neurodegenerative diseases primarily associated with aging becomes more pressing than ever. In 2017, we celebrate a grim 200th anniversary since the very first description of Parkinson’s disease (PD) and its related symptomatology. Two centuries after this debilitating disease was first identified, finding a cure remains a hopeful goal rather than an attainable objective on the horizon. Tireless work has provided insight into the characterization and progression of the disease down to a molecular level. We now know that the main motor deficits associated with PD arise from the almost total loss of dopaminergic cells in the substantia nigra pars compacta. A concomitant loss of cholinergic cells entails a cognitive decline in these patients, and current therapies are only partially effective, often inducing side-effects after a prolonged treatment. This review covers some of the recent developments in the field of Basal Ganglia (BG) function in physiology and pathology, with a particular focus on the two main neuromodulatory systems known to be severely affected in PD, highlighting some of the remaining open question from three main stand points:- Heterogeneity of midbrain dopamine neurons.- Pairing of dopamine (DA) sub-circuits.- Dopamine-Acetylcholine (ACh) interaction.A vast amount of knowledge has been accumulated over the years from experimental conditions, but very little of it is reflected or used at a translational or clinical level. An initiative to implement the knowledge that is emerging from circuit-based approaches to tackle neurodegenerative disorders like PD will certainly be tremendously beneficial.

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Differential Control of Dopaminergic Excitability and Locomotion by Cholinergic Inputs in Mouse Substantia Nigra

Cited by 31 publications

References 36 publications

Circadian and Homeostatic Modulation of Multi-Unit Activity in Midbrain Dopaminergic Structures

Circadian and Homeostatic Modulation of Multi-Unit Activity in Midbrain Dopaminergic Structures

Neurodegenerative Diseases – Is Metabolic Deficiency the Root Cause?

Dopamine and Acetylcholine, a Circuit Point of View in Parkinson’s Disease

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