scholarly journals Output-Specific Adaptation of Habenula-Midbrain Excitatory Synapses During Cocaine Withdrawal

2021 ◽  
Vol 13 ◽  
Author(s):  
Joseph Clerke ◽  
Patricia Preston-Ferrer ◽  
Ioannis S. Zouridis ◽  
Audrey Tissot ◽  
Laura Batti ◽  
...  
Keyword(s):  
Prefrontal Cortex ◽  
Glutamate Release ◽  
Synaptic Connectivity ◽  
Excitatory Synapses ◽  
Medial Aspect ◽  
Cocaine Withdrawal ◽  
Lateral Habenula ◽  
Specific Adaptation ◽  
Neuronal Populations ◽  
Presynaptic Release

Projections from the lateral habenula (LHb) control ventral tegmental area (VTA) neuronal populations’ activity and both nuclei shape the pathological behaviors emerging during cocaine withdrawal. However, it is unknown whether cocaine withdrawal modulates LHb neurotransmission onto subsets of VTA neurons that are part of distinct neuronal circuits. Here we show that, in mice, cocaine withdrawal, drives discrete and opposing synaptic adaptations at LHb inputs onto VTA neurons defined by their output synaptic connectivity. LHb axons innervate the medial aspect of VTA, release glutamate and synapse on to dopamine and non-dopamine neuronal populations. VTA neurons receiving LHb inputs project their axons to medial prefrontal cortex (mPFC), nucleus accumbens (NAc), and lateral hypothalamus (LH). While cocaine withdrawal increases glutamate release from LHb onto VTA-mPFC projectors, it reduces presynaptic release onto VTA-NAc projectors, leaving LHb synapses onto VTA-to-LH unaffected. Altogether, cocaine withdrawal promotes distinct adaptations at identified LHb-to-VTA circuits, which provide a framework for understanding the circuit basis of the negative states emerging during abstinence of drug intake.

scholarly journals Nanoscale co-organization and coactivation of AMPAR, NMDAR, and mGluR at excitatory synapses

2020 ◽  
Vol 117 (25) ◽  
pp. 14503-14511 ◽  
Author(s):  
Julia Goncalves ◽  
Tomas M. Bartol ◽  
Côme Camus ◽  
Florian Levet ◽  
Ana Paula Menegolla ◽  
...  
Keyword(s):  
Glutamate Receptor ◽  
Single Molecule ◽  
Glutamate Release ◽  
Neurotransmitter Receptors ◽  
Excitatory Synapses ◽  
Superresolution Microscopy ◽  
Synaptic Physiology ◽  
Transmission Properties ◽  
Presynaptic Release ◽  
Average Quantity

The nanoscale co-organization of neurotransmitter receptors facing presynaptic release sites is a fundamental determinant of their coactivation and of synaptic physiology. At excitatory synapses, how endogenous AMPARs, NMDARs, and mGluRs are co-organized inside the synapse and their respective activation during glutamate release are still unclear. Combining single-molecule superresolution microscopy, electrophysiology, and modeling, we determined the average quantity of each glutamate receptor type, their nanoscale organization, and their respective activation. We observed that NMDARs form a unique cluster mainly at the center of the PSD, while AMPARs segregate in clusters surrounding the NMDARs. mGluR5 presents a different organization and is homogenously dispersed at the synaptic surface. From these results, we build a model predicting the synaptic transmission properties of a unitary synapse, allowing better understanding of synaptic physiology.

scholarly journals The Trace Kynurenine, Cinnabarinic Acid, Displays Potent Antipsychotic-Like Activity in Mice and Its Levels Are Reduced in the Prefrontal Cortex of Individuals Affected by Schizophrenia

2020 ◽  
Vol 46 (6) ◽  
pp. 1471-1481 ◽  
Author(s):  
Martina Ulivieri ◽  
Joanna Monika Wierońska ◽  
Luana Lionetto ◽  
Katiuscia Martinello ◽  
Paulina Cieslik ◽  
...  
Keyword(s):  
Prefrontal Cortex ◽  
Metabotropic Glutamate Receptors ◽  
Systemic Treatment ◽  
Glutamate Release ◽  
Ultra Performance Liquid Chromatography ◽  
Human Brain Tissue ◽  
Metabotropic Glutamate ◽  
Chromatography Tandem Mass Spectrometry ◽  
Highly Sensitive ◽  
Liquid Chromatography Tandem Mass

Abstract Cinnabarinic acid (CA) is a kynurenine metabolite that activates mGlu4 metabotropic glutamate receptors. Using a highly sensitive ultra-performance liquid chromatography/tandem mass spectrometry (UPLC/MS-MS) method, we found that CA is present in trace amounts in human brain tissue. CA levels were largely reduced in the prefrontal cortex (PFC) of individuals affected by schizophrenia. This reduction did not correlate with age, sex, duration of the disease, and duration and type of antipsychotic medication and might, therefore, represent a trait of schizophrenia. Interestingly, systemic treatment with low doses of CA (<1 mg/kg, i.p.) showed robust efficacy in several behavioral tests useful to study antipsychotic-like activity in mice and rats and attenuated MK-801-evoked glutamate release. CA failed to display antipsychotic-like activity and inhibit excitatory synaptic transmission in mice lacking mGlu4 receptors. These findings suggest that CA is a potent endogenous antipsychotic-like molecule and reduced CA levels in the PFC might contribute to the pathophysiology of schizophrenia.

scholarly journals Second-by-second analysis of alpha 7 nicotine receptor regulation of glutamate release in the prefrontal cortex of awake rats

Synapse ◽  
2009 ◽  
Vol 63 (12) ◽  
pp. 1069-1082 ◽  
Author(s):  
Åsa Konradsson-Geuken ◽  
Clelland R. Gash ◽  
Kathleen Alexander ◽  
Francois Pomerleau ◽  
Peter Huettl ◽  
...  
Keyword(s):  
Prefrontal Cortex ◽  
Glutamate Release ◽  
Receptor Regulation ◽  
Nicotine Receptor ◽  
Alpha 7 ◽  
Awake Rats

scholarly journals Suppression of Parvalbumin Interneuron Activity in the Prefrontal Cortex Recapitulates Features of Impaired Excitatory/Inhibitory Balance and Sensory Processing in Schizophrenia

2020 ◽  
Vol 46 (4) ◽  
pp. 981-989 ◽  
Author(s):  
Oana Toader ◽  
Moritz von Heimendahl ◽  
Niklas Schuelert ◽  
Wiebke Nissen ◽  
Holger Rosenbrock
Keyword(s):  
Prefrontal Cortex ◽  
Signal To Noise Ratio ◽  
Treatment Options ◽  
Brain Regions ◽  
Inhibitory Interneuron ◽  
Network Activity ◽  
Limiting Factor ◽  
Neuronal Populations ◽  
Parvalbumin Interneuron ◽  
New Treatment

Abstract Accumulating evidence supports parvalbumin expressing inhibitory interneuron (PV IN) dysfunction in the prefrontal cortex as a cause for cognitive impairment associated with schizophrenia (CIAS). PV IN decreased activity is suggested to be the culprit for many of the EEG deficits measured in patients, which correlate with deficits in working memory (WM), cognitive flexibility and attention. In the last few decades, CIAS has been recognized as a heavy burden on the quality of life of patients with schizophrenia, but little progress has been made in finding new treatment options. An important limiting factor in this process is the lack of adequate preclinical models and an incomplete understanding of the circuits engaged in cognition. In this study, we back-translated an auditory stimulation protocol regularly used in human EEG studies into mice and combined it with optogenetics to investigate the role of prefrontal cortex PV INs in excitatory/inhibitory balance and cortical processing. We also assessed spatial WM and reversal learning (RL) during inhibition of prefrontal cortex PV INs. We found significant impairments in trial-to-trial reliability, increased basal network activity and increased oscillation power at 20–60 Hz, and a decreased signal-to-noise ratio, but no significant impairments in behavior. These changes reflect some but not all neurophysiological deficits seen in patients with schizophrenia, suggesting that other neuronal populations and possibly brain regions are involved as well. Our work supports and expands previous findings and highlights the versatility of an approach that combines innovative technologies with back-translated tools used in humans.

scholarly journals Time-invariant working memory representations in the presence of code-morphing in the lateral prefrontal cortex

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Aishwarya Parthasarathy ◽  
Cheng Tang ◽  
Roger Herikstad ◽  
Loong Fah Cheong ◽  
Shih-Cheng Yen ◽  
...  
Keyword(s):  
Working Memory ◽  
Prefrontal Cortex ◽  
Dimensional Subspace ◽  
Neural Data ◽  
Neuronal Populations ◽  
Attractor Model ◽  
Memory Representations ◽  
Low Dimensional ◽  
Types Of Information ◽  
Time Invariant

Abstract Maintenance of working memory is thought to involve the activity of prefrontal neuronal populations with strong recurrent connections. However, it was recently shown that distractors evoke a morphing of the prefrontal population code, even when memories are maintained throughout the delay. How can a morphing code maintain time-invariant memory information? We hypothesized that dynamic prefrontal activity contains time-invariant memory information within a subspace of neural activity. Using an optimization algorithm, we found a low-dimensional subspace that contains time-invariant memory information. This information was reduced in trials where the animals made errors in the task, and was also found in periods of the trial not used to find the subspace. A bump attractor model replicated these properties, and provided predictions that were confirmed in the neural data. Our results suggest that the high-dimensional responses of prefrontal cortex contain subspaces where different types of information can be simultaneously encoded with minimal interference.

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