scholarly journals Functional dissection of basal ganglia inhibitory input onto SNc dopaminergic neurons

2019 ◽  
Author(s):  
RC Evans ◽  
EL Twedell ◽  
M Zhu ◽  
J Ascencio ◽  
R Zhang ◽  
...  
Keyword(s):  
Basal Ganglia ◽  
Dopaminergic Neurons ◽  
Firing Pattern ◽  
Dorsal Striatum ◽  
Excitatory Input ◽  
Dopamine Neurons ◽  
Inhibitory Input ◽  
Brain Areas ◽  
Aversive Events ◽  
Rebound Firing

AbstractSubstania nigra (SNc) dopaminergic neurons show a pause-rebound firing pattern in response to aversive events. Because these neurons integrate information from predominately inhibitory brain areas, it is important to determine which inputs functionally inhibit the dopamine neurons and whether this pause-rebound firing pattern can be produced by a solely inhibitory input. Here, we functionally map genetically-defined inhibitory projections from the dorsal striatum (striosome and matrix) and globus pallidus (GPe; parvalbumin and Lhx6) onto SNc neurons. We find that GPe and striosomal inputs both pause firing in SNc neurons, but rebound firing only occurs after inhibition from striosomes. Indeed, we find that striosomes are synaptically optimized to produce rebound and preferentially inhibit a subpopulation of ventral, intrinsically rebound-ready SNc dopaminergic neurons on their reticulata dendrites. Therefore, we describe a self-contained dendrite-specific striatonigral circuit that can produce pause-rebound firing in the absence of excitatory input.

scholarly journals Intrinsic Dynamics in Neuronal Networks. I. Theory

2000 ◽  
Vol 83 (2) ◽  
pp. 808-827 ◽  
Author(s):  
P. E. Latham ◽  
B. J. Richmond ◽  
P. G. Nelson ◽  
S. Nirenberg
Keyword(s):  
Firing Rate ◽  
Firing Pattern ◽  
Neuronal Networks ◽  
Network Connectivity ◽  
Excitatory Input ◽  
High Rate ◽  
Inhibitory Neurons ◽  
Inhibitory Input ◽  
Dynamic Interactions ◽  
Firing Patterns

Many networks in the mammalian nervous system remain active in the absence of stimuli. This activity falls into two main patterns: steady firing at low rates and rhythmic bursting. How are these firing patterns generated? Specifically, how do dynamic interactions between excitatory and inhibitory neurons produce these firing patterns, and how do networks switch from one firing pattern to the other? We investigated these questions theoretically by examining the intrinsic dynamics of large networks of neurons. Using both a semianalytic model based on mean firing rate dynamics and simulations with large neuronal networks, we found that the dynamics, and thus the firing patterns, are controlled largely by one parameter, the fraction of endogenously active cells. When no endogenously active cells are present, networks are either silent or fire at a high rate; as the number of endogenously active cells increases, there is a transition to bursting; and, with a further increase, there is a second transition to steady firing at a low rate. A secondary role is played by network connectivity, which determines whether activity occurs at a constant mean firing rate or oscillates around that mean. These conclusions require only conventional assumptions: excitatory input to a neuron increases its firing rate, inhibitory input decreases it, and neurons exhibit spike-frequency adaptation. These conclusions also lead to two experimentally testable predictions: 1) isolated networks that fire at low rates must contain endogenously active cells and 2) a reduction in the fraction of endogenously active cells in such networks must lead to bursting.

scholarly journals Angiotensin-II modulates GABAergic neurotransmission in the mouse substantia nigra

2021 ◽  
Author(s):  
Maibam R. Singh ◽  
Jozsef Vigh ◽  
Gregory C. Amberg
Keyword(s):  
Angiotensin Ii ◽  
Basal Ganglia ◽  
Substantia Nigra ◽  
Neuronal Activity ◽  
Dopaminergic Neurons ◽  
Gabaergic Neurons ◽  
Inhibitory Input ◽  
Ang Ii ◽  
Signaling Mechanism ◽  
Gabaergic Neurotransmission

ABSTRACTGABAergic projections neurons of the substantia nigra reticulata (SNr), through an extensive network of dendritic arbors and axon collaterals, provide robust inhibitory input to neighboring dopaminergic neurons in the substantia nigra compacta (SNc). Angiotensin-II (Ang-II) receptor signaling increases SNc dopaminergic neuronal sensitivity to insult, thus rendering these cells susceptible to dysfunction and destruction. However, the mechanisms by which Ang-II regulates SNc dopaminergic neuronal activity are unclear. Given the complex relationship between SN dopaminergic and GABAergic neurons, we hypothesized that Ang-II could regulate SNc dopaminergic neuronal activity directly and indirectly by modulating SNr GABAergic neurotransmission. Herein, using transgenic mice, slice electrophysiology, and optogenetics, we provide evidence of an AT1 receptor-mediated signaling mechanism in SNr GABAergic neurons where Ang-II suppresses electrically-evoked neuronal output by facilitating postsynaptic GABAA receptors and prolonging the action potential duration. Unexpectedly, Ang-II had no discernable effects on the electrical properties of SNc dopaminergic neurons. Also, and indicating a nonlinear relationship between electrical activity and neuronal output, following phasic photoactivation of SNr GABAergic neurons, Ang-II paradoxically enhanced the feedforward inhibitory input to SNc dopaminergic neurons. In sum, our observations describe an increasingly complex and heterogeneous response of the SN to Ang-II by revealing cell-specific responses and nonlinear effects on intranigral GABAergic neurotransmission. Our data further implicate the renin-angiotensin-system as a functionally relevant neuromodulator in the basal ganglia, thus underscoring a need for additional inquiry.SIGNIFICANCE STATEMENTAngiotensin II (Ang-II) promotes dopamine release in the striatum and, in the substantia nigra compacta (SNc), exacerbates dopaminergic cell loss in animal models of Parkinson’s disease. Despite a potential association with Parkinson’s disease, the effects of Ang-II on neuronal activity in the basal ganglia is unknown. Here we describe a novel AT1 receptor-dependent signaling mechanism in GABAergic projection neurons of the SN reticulata (SNr), a major inhibitory regulator of SNc dopaminergic neurons. Specifically, Ang-II suppresses SNr GABAergic neuronal activity, subsequently altering GABAergic modulation of SNc dopaminergic neurons in a nonlinear fashion. Altogether, our data provide the first indication of Ang-II-dependent modulation of GABAergic neurotransmission in the SN, which could impact output from the basal ganglia in health and disease.

scholarly journals The tectonigral pathway regulates appetitive locomotion in predatory hunting in mice

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Meizhu Huang ◽  
Dapeng Li ◽  
Xinyu Cheng ◽  
Qing Pei ◽  
Zhiyong Xie ◽  
...  
Keyword(s):  
Substantia Nigra ◽  
Superior Colliculus ◽  
Dopamine Release ◽  
Dorsal Striatum ◽  
Dopamine Neurons ◽  
Substantia Nigra Pars Compacta ◽  
Neuronal Circuitry ◽  
Locomotion Speed ◽  
Brain Circuit ◽  
Goal Directed Behavior

AbstractAppetitive locomotion is essential for animals to approach rewards, such as food and prey. The neuronal circuitry controlling appetitive locomotion is unclear. In a goal-directed behavior—predatory hunting, we show an excitatory brain circuit from the superior colliculus (SC) to the substantia nigra pars compacta (SNc) to enhance appetitive locomotion in mice. This tectonigral pathway transmits locomotion-speed signals to dopamine neurons and triggers dopamine release in the dorsal striatum. Synaptic inactivation of this pathway impairs appetitive locomotion but not defensive locomotion. Conversely, activation of this pathway increases the speed and frequency of approach during predatory hunting, an effect that depends on the activities of SNc dopamine neurons. Together, these data reveal that the SC regulates locomotion-speed signals to SNc dopamine neurons to enhance appetitive locomotion in mice.

scholarly journals α-Synuclein-induced dysregulation of neuronal activity contributes to murine dopamine neuron vulnerability

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Abeer Dagra ◽  
Douglas R. Miller ◽  
Min Lin ◽  
Adithya Gopinath ◽  
Fatemeh Shaerzadeh ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Neuronal Activity ◽  
Dopaminergic Neurons ◽  
Prolonged Exposure ◽  
D2 Receptor ◽  
Neuronal Firing ◽  
Dopamine Neurons ◽  
Loss Of Function ◽  
Therapeutic Implications

AbstractPathophysiological damages and loss of function of dopamine neurons precede their demise and contribute to the early phases of Parkinson’s disease. The presence of aberrant intracellular pathological inclusions of the protein α-synuclein within ventral midbrain dopaminergic neurons is one of the cardinal features of Parkinson’s disease. We employed molecular biology, electrophysiology, and live-cell imaging to investigate how excessive α-synuclein expression alters multiple characteristics of dopaminergic neuronal dynamics and dopamine transmission in cultured dopamine neurons conditionally expressing GCaMP6f. We found that overexpression of α-synuclein in mouse (male and female) dopaminergic neurons altered neuronal firing properties, calcium dynamics, dopamine release, protein expression, and morphology. Moreover, prolonged exposure to the D2 receptor agonist, quinpirole, rescues many of the alterations induced by α-synuclein overexpression. These studies demonstrate that α-synuclein dysregulation of neuronal activity contributes to the vulnerability of dopaminergic neurons and that modulation of D2 receptor activity can ameliorate the pathophysiology. These findings provide mechanistic insights into the insidious changes in dopaminergic neuronal activity and neuronal loss that characterize Parkinson’s disease progression with significant therapeutic implications.

scholarly journals Crucial Role of FABP3 in αSyn-Induced Reduction of Septal GABAergic Neurons and Cognitive Decline in Mice

2021 ◽  
Vol 22 (1) ◽  
pp. 400
Author(s):  
Kazuya Matsuo ◽  
Yasushi Yabuki ◽  
Ronald Melki ◽  
Luc Bousset ◽  
Yuji Owada ◽  
...  
Keyword(s):  
Cognitive Impairment ◽  
Cognitive Decline ◽  
Cognitive Processing ◽  
Dopaminergic Neurons ◽  
Dorsal Striatum ◽  
Cholinergic Neurons ◽  
Medial Septum ◽  
Gabaergic Neurons ◽  
Gamma Aminobutyric Acid ◽  
Fatty Acid Binding

In synucleinopathies, while motor symptoms are thought to be attributed to the accumulation of misfolded α-synuclein (αSyn) in nigral dopaminergic neurons, it remains to be elucidated how cognitive decline arises. Here, we investigated the effects of distinct αSyn strains on cognition and the related neuropathology in the medial septum/diagonal band (MS/DB), a key region for cognitive processing. Bilateral injection of αSyn fibrils into the dorsal striatum potently impaired cognition in mice. The cognitive decline was accompanied by accumulation of phosphorylated αSyn at Ser129 and reduction of gamma-aminobutyric acid (GABA)-ergic but not cholinergic neurons in the MS/DB. Since we have demonstrated that fatty acid-binding protein 3 (FABP3) is critical for αSyn neurotoxicity in nigral dopaminergic neurons, we investigated whether FABP3 also participates in αSyn pathology in the MS/DB and cognitive decline. FABP3 was highly expressed in GABAergic but rarely in cholinergic neurons in the MS/DB. Notably, Fabp3 deletion antagonized the accumulation of phosphorylated αSyn, decrease in GABAergic neurons, and cognitive impairment caused by αSyn fibrils. Overall, the present study indicates that FABP3 mediates αSyn neurotoxicity in septal GABAergic neurons and the resultant cognitive impairment, and that FABP3 in this subpopulation could be a therapeutic target for dementia in synucleinopathies.

scholarly journals Deep brain stimulation of the subthalamic nucleus reestablishes neuronal information transmission in the 6-OHDA rat model of parkinsonism

2014 ◽  
Vol 111 (10) ◽  
pp. 1949-1959 ◽  
Author(s):  
Alan D. Dorval ◽  
Warren M. Grill
Keyword(s):  
Deep Brain Stimulation ◽  
Basal Ganglia ◽  
Information Transmission ◽  
Brain Stimulation ◽  
Rat Model ◽  
Information Transfer ◽  
Firing Pattern ◽  
Signal Propagation ◽  
Neuronal Firing ◽  
Deep Brain

Pathophysiological activity of basal ganglia neurons accompanies the motor symptoms of Parkinson's disease. High-frequency (>90 Hz) deep brain stimulation (DBS) reduces parkinsonian symptoms, but the mechanisms remain unclear. We hypothesize that parkinsonism-associated electrophysiological changes constitute an increase in neuronal firing pattern disorder and a concomitant decrease in information transmission through the ventral basal ganglia, and that effective DBS alleviates symptoms by decreasing neuronal disorder while simultaneously increasing information transfer through the same regions. We tested these hypotheses in the freely behaving, 6-hydroxydopamine-lesioned rat model of hemiparkinsonism. Following the onset of parkinsonism, mean neuronal firing rates were unchanged, despite a significant increase in firing pattern disorder (i.e., neuronal entropy), in both the globus pallidus and substantia nigra pars reticulata. This increase in neuronal entropy was reversed by symptom-alleviating DBS. Whereas increases in signal entropy are most commonly indicative of similar increases in information transmission, directed information through both regions was substantially reduced (>70%) following the onset of parkinsonism. Again, this decrease in information transmission was partially reversed by DBS. Together, these results suggest that the parkinsonian basal ganglia are rife with entropic activity and incapable of functional information transmission. Furthermore, they indicate that symptom-alleviating DBS works by lowering the entropic noise floor, enabling more information-rich signal propagation. In this view, the symptoms of parkinsonism may be more a default mode, normally overridden by healthy basal ganglia information. When that information is abolished by parkinsonian pathophysiology, hypokinetic symptoms emerge.

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.

Binaural processing of sound pressure level in the inferior colliculus

1987 ◽  
Vol 57 (4) ◽  
pp. 1130-1147 ◽  
Author(s):  
M. N. Semple ◽  
L. M. Kitzes
Keyword(s):  
Inferior Colliculus ◽  
Sound Pressure ◽  
Spatial Information ◽  
Discharge Rate ◽  
Excitatory Input ◽  
Central Nucleus ◽  
Intensity Difference ◽  
Inhibitory Input ◽  
Directional Information ◽  
Discharge Rates

The central auditory system could encode information about the location of a high-frequency sound source by comparing the sound pressure levels at the ears. Two potential computations are the interaural intensity difference (IID) and the average binaural intensity (ABI). In this study of the central nucleus of the inferior colliculus (ICC) of the anesthetized gerbil, we demonstrate that responses of 85% of the 97 single units in our sample were jointly influenced by IID and ABI. For a given ABI, discharge rate of most units is a sigmoidal function of IID, and peak rates occur at IIDs favoring the contralateral ear. Most commonly, successive increments of ABI cause successive shifts of the IID functions toward IIDs favoring the ipsilateral ear. Neurons displaying this behavior include many that would conventionally be classified EI (receiving predominantly excitatory input arising from one ear and inhibitory input from the other), many that would be classified EE (receiving predominantly excitatory input arising from each ear), and all that are responsive only to contralateral stimulation. The IID sensitivity of a very few EI neurons is unaffected by ABI, except near threshold. Such units could provide directional information that is independent of source intensity. A few EE neurons are very sensitive to ABI, but are minimally sensitive to IID. Nevertheless, our data indicate that responses of most EE units in ICC are strongly dominated by excitation of contralateral origin. For some units, discharge rate is nonmonotonically related to IID and is maximal when the stimuli at the two ears are of comparable sound pressure. This preference for zero IID is common for all binaural levels. Many EI neurons respond nonmonotonically to ABI. Discharge rates are greater for IIDs representative of contralateral space and are maximal at a single best ABI. For a subset of these neurons, the influence arising from the ipsilateral ear is comprised of a mixture of excitation and inhibition. As a consequence, discharge rates are nonmonotonically related not only to ABI but also to IID. This dual nonmonotonicity creates a clear focus of peak response at a particular ABI/IID combination. Because of their mixed monaural influences, such units would be ascribed to different classes of the conventional (EE/EI) binaural classification scheme depending on the binaural level presented. Several response classes were identified in this study, and each might contribute differently to the encoding of spatial information.(ABSTRACT TRUNCATED AT 400 WORDS)

scholarly journals Changes in excitability properties of ventromedial motor thalamic neurons in 6-OHDA lesioned mice

2020 ◽  
Author(s):  
Edyta K Bichler ◽  
Francesco Cavarretta ◽  
Dieter Jaeger
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Basal Ganglia ◽  
Potassium Current ◽  
Cellular Level ◽  
Inhibitory Input ◽  
Dopamine Depletion ◽  
Thalamic Nuclei ◽  
Adult Mice ◽  
Motor Thalamus

AbstractThe activity of basal ganglia input receiving motor thalamus (BGMT) makes a critical impact on motor cortical processing, but modification in BGMT processing with Parkinsonian conditions have not be investigated at the cellular level. Such changes may well be expected due to homeostatic regulation of neural excitability in the presence of altered synaptic drive with dopamine depletion. We addressed this question by comparing BGMT properties in brain slice recordings between control and unilaterally 6-OHDA treated adult mice. At a minimum of 1 month post 6-OHDA treatment, BGMT neurons showed a highly significant increase in intrinsic excitability, which was primarily due to a decrease in M-type potassium current. BGMT neurons after 6-OHDA treatment also showed an increase in T-type calcium rebound spikes following hyperpolarizing current steps. Biophysical computer modeling of a thalamic neuron demonstrated that an increase in rebound spiking can also be accounted for by a decrease in the M-type potassium current. Modeling also showed that an increase in sag with hyperpolarizing steps found after 6-OHDA treatment could in part but not fully be accounted for by the decrease in M-type current. These findings support the hypothesis that homeostatic changes in BGMT neural properties following 6-OHDA treatment likely influence the signal processing taking place in basal ganglia thalamocortical processing in Parkinson’s disease.Significance StatementOur investigation of the excitability properties of neurons in the basal ganglia input receiving motor thalamus (BGMT) is significant because they are likely to be different from properties in other thalamic nuclei due to the additional inhibitory input stream these neurons receive. Further, they are important to understand the role of BGMT in the dynamic dysfunction of cortico – basal ganglia circuits in Parkinson’s disease. We provide clear evidence that after 6-OHDA treatment of mice important homeostatic changes occur in the intrinsic properties of BGMT neurons. Specifically we identify the M-type potassium current as an important thalamic excitability regulator in the parkinsonian state.

scholarly journals Midbrain dopamine neurons signal aversion in a reward-context-dependent manner

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Hideyuki Matsumoto ◽  
Ju Tian ◽  
Naoshige Uchida ◽  
Mitsuko Watabe-Uchida
Keyword(s):  
Dopamine Neurons ◽  
Prediction Errors ◽  
Dependent Manner ◽  
Value Prediction ◽  
Signal Value ◽  
Aversive Events ◽  
High Reward ◽  
Midbrain Dopamine ◽  
Dopamine Signaling ◽  
Reward And Punishment

Dopamine is thought to regulate learning from appetitive and aversive events. Here we examined how optogenetically-identified dopamine neurons in the lateral ventral tegmental area of mice respond to aversive events in different conditions. In low reward contexts, most dopamine neurons were exclusively inhibited by aversive events, and expectation reduced dopamine neurons’ responses to reward and punishment. When a single odor predicted both reward and punishment, dopamine neurons’ responses to that odor reflected the integrated value of both outcomes. Thus, in low reward contexts, dopamine neurons signal value prediction errors (VPEs) integrating information about both reward and aversion in a common currency. In contrast, in high reward contexts, dopamine neurons acquired a short-latency excitation to aversive events that masked their VPE signaling. Our results demonstrate the importance of considering the contexts to examine the representation in dopamine neurons and uncover different modes of dopamine signaling, each of which may be adaptive for different environments.

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