GABA—from Inhibition to Cognition: Emerging Concepts

Neural functioning and plasticity can be studied on different levels of organization and complexity ranging from the molecular and synaptic level to neural circuitry of whole brain networks. Across neuroscience different methods are being applied to better understand the role of various neurotransmitter systems in the evolution of perception and cognition. GABA is the main inhibitory neurotransmitter in the adult mammalian brain and, depending on the brain region, up to 25% of the total number of cortical neurons are GABAergic interneurons. At the one end of the spectrum, GABAergic neurons have been accurately described with regard to cell morphological, molecular, and electrophysiological properties; at the other end researchers try to link GABA concentrations in specific brain regions to human behavior using magnetic resonance spectroscopy. One of the main challenges of modern neuroscience currently is to integrate knowledge from highly specialized subfields at distinct biological scales into a coherent picture that bridges the gap between molecules and behavior. In the current review, recent findings from different fields of GABA research are summarized delineating a potential strategy to develop a more holistic picture of the function and role of GABA.

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Taste quality representation in the human brain

10.1101/726711 ◽

2019 ◽

Author(s):

Jason A. Avery ◽

Alexander G. Liu ◽

John E. Ingeholm ◽

Cameron D. Riddell ◽

Stephen J. Gotts ◽

...

Keyword(s):

Human Brain ◽

Cortical Neurons ◽

Brain Regions ◽

Taste Quality ◽

7 Tesla ◽

Mammalian Brain ◽

High Magnetic Field Strength ◽

Magnetic Resonance Imaging Mri ◽

Spatial Locations ◽

Univariate Analyses

SUMMARYIn the mammalian brain, the insula is the primary cortical substrate involved in the perception of taste. Recent imaging studies in rodents have identified a gustotopic organization in the insula, whereby distinct insula regions are selectively responsive to one of the five basic tastes. However, numerous studies in monkeys have reported that gustatory cortical neurons are broadly-tuned to multiple tastes, and tastes are not represented in discrete spatial locations. Neuroimaging studies in humans have thus far been unable to discern between these two models, though this may be due to the relatively low spatial resolution employed in taste studies to date. In the present study, we examined the spatial representation of taste within the human brain using ultra-high resolution functional magnetic resonance imaging (MRI) at high magnetic field strength (7-Tesla). During scanning, participants tasted sweet, salty, sour and tasteless liquids, delivered via a custom-built MRI-compatible tastant-delivery system. Our univariate analyses revealed that all tastes (vs. tasteless) activated primary taste cortex within the bilateral dorsal mid-insula, but no brain region exhibited a consistent preference for any individual taste. However, our multivariate searchlight analyses were able to reliably decode the identity of distinct tastes within those mid-insula regions, as well as brain regions involved in affect and reward, such as the striatum, orbitofrontal cortex, and amygdala. These results suggest that taste quality is not represented topographically, but by a combinatorial spatial code, both within primary taste cortex as well as regions involved in processing the hedonic and aversive properties of taste.

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AMPed-up adolescents: the role of age in the abuse of amphetamines and its consequences on cognition and prefrontal cortex development

10.31219/osf.io/t58qe ◽

2020 ◽

Author(s):

Sara Ruth Westbrook ◽

Lauren Carrica ◽

Asia Banks ◽

Joshua Michael Gulley

Keyword(s):

Prefrontal Cortex ◽

Animal Studies ◽

Drug Effects ◽

Epidemiological Studies ◽

Brain Regions ◽

Vulnerability Factors ◽

Brain And Behavior ◽

And Behavior ◽

Detrimental Impact

Adolescent use of amphetamine and its closely related, methylated version methamphetamine, is alarmingly high in those who use drugs for nonmedical purposes. This raises serious concerns about the potential for this drug use to have a long-lasting, detrimental impact on the normal development of the brain and behavior that is ongoing during adolescence. In this review, we explore recent findings from both human and laboratory animal studies that investigate the consequences of amphetamine and methamphetamine exposure during this stage of life. We highlight studies that assess sex differences in adolescence, as well as those that are designed specifically to address the potential unique effects of adolescent exposure by including groups at other life stages (typically young adulthood). We consider epidemiological studies on age and sex as vulnerability factors for developing problems with the use of amphetamines, as well as human and animal laboratory studies that tap into age differences in use, its short-term effects on behavior, and the long-lasting consequences of this exposure on cognition. We also focus on studies of drug effects in the prefrontal cortex, which is known to be critically important for cognition and is among the later maturing brain regions. Finally, we discuss important issues that should be addressed in future studies so that the field can further our understanding of the mechanisms underlying adolescent use of amphetamines and its outcomes on the developing brain and behavior.

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Excitatory/inhibitory neuronal metabolic balance in mouse hippocampus upon infusion of [U-13C6]glucose

Journal of Cerebral Blood Flow & Metabolism ◽

10.1177/0271678x20910535 ◽

2020 ◽

pp. 0271678X2091053

Author(s):

Antoine Cherix ◽

Guillaume Donati ◽

Blanca Lizarbe ◽

Bernard Lanz ◽

Carole Poitry-Yamate ◽

...

Keyword(s):

Critical Role ◽

Tca Cycle ◽

Brain Regions ◽

Inhibitory Neurons ◽

Resonance Spectroscopy ◽

Spectral Fitting ◽

Mouse Hippocampus ◽

And Behavior ◽

Gabaergic Activity

Hippocampus plays a critical role in linking brain energetics and behavior typically associated to stress exposure. In this study, we aimed to simultaneously assess excitatory and inhibitory neuronal metabolism in mouse hippocampus in vivo by applying 18FDG-PET and indirect 13C magnetic resonance spectroscopy (1H-[13C]-MRS) at 14.1 T upon infusion of uniformly 13C-labeled glucose ([U-13C6]Glc). Improving the spectral fitting by taking into account variable decoupling efficiencies of [U-13C6]Glc and refining the compartmentalized model by including two γ-aminobutyric acid (GABA) pools permit us to evaluate the relative contributions of glutamatergic and GABAergic metabolism to total hippocampal neuroenergetics. We report that GABAergic activity accounts for ∼13% of total neurotransmission (VNT) and ∼27% of total neuronal TCA cycle (VTCA) in mouse hippocampus suggesting a higher VTCA/VNT ratio for inhibitory neurons compared to excitatory neurons. Finally, our results provide new strategies and tools for bringing forward the developments and applications of 13C-MRS in specific brain regions of small animals.

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Brain glutamate in medication-free depressed patients: a proton MRS study at 7 Tesla

Psychological Medicine ◽

10.1017/s0033291717003373 ◽

2017 ◽

Vol 48 (10) ◽

pp. 1731-1737 ◽

Cited By ~ 10

Author(s):

Beata R. Godlewska ◽

Charles Masaki ◽

Ann L. Sharpley ◽

Philip J. Cowen ◽

Uzay E. Emir

Keyword(s):

Basal Ganglia ◽

Occipital Cortex ◽

Brain Regions ◽

Anterior Cingulate ◽

7 Tesla ◽

Resonance Spectroscopy ◽

Depressed Patients ◽

Water Signal ◽

Significant Difference

BackgroundThe possible role of glutamate in the pathophysiology and treatment of depression is of intense current interest. Proton magnetic resonance spectroscopy (MRS) enables the detection of glutamate in the living human brain and meta-analyses of previous MRS studies in depressed patients have suggested that glutamate levels are decreased in anterior brain regions. Nevertheless, at conventional magnetic field strengths [1.5–3 Tesla (T)], it is difficult to separate glutamate from its metabolite and precursor, glutamine, with the two often being measured together as Glx. In contrast, MRS at 7 T allows clear spectral resolution of glutamate and glutamine.MethodWe studied 55 un-medicated depressed patients and 50 healthy controls who underwent MRS scanning at 7 T with voxels placed in anterior cingulate cortex, occipital cortex and putamen (PUT). Neurometabolites were calculated using the unsuppressed water signal as a reference.ResultsCompared with controls, depressed patients showed no significant difference in glutamate in any of the three voxels studied; however, glutamine concentrations in the patients were elevated by about 12% in the PUT (p < 0.001).ConclusionsThe increase in glutamine in PUT is of interest in view of the postulated role of the basal ganglia in the neuropsychology of depression and is consistent with elevated activity in the descending cortical glutamatergic innervation to the PUT. The basal ganglia have rarely been the subject of MRS investigations in depressed patients and further MRS studies of these structures in depression are warranted.

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Cannabis use decreases prefrontal glutamate levels in early psychosis

European Psychiatry ◽

10.1016/j.eurpsy.2017.02.324 ◽

2017 ◽

Vol 41 (S1) ◽

pp. S349-S350 ◽

Cited By ~ 1

Author(s):

S. Rigucci ◽

L. Xin ◽

P. Klauser ◽

P.S. Baumann ◽

L. Alameda ◽

...

Keyword(s):

Chronic Schizophrenia ◽

Brain Regions ◽

Cannabis Use ◽

Resonance Spectroscopy ◽

Critical Question ◽

Prodromal Phase ◽

Correlative Analysis ◽

Increased Risk ◽

Competing Interest

Recent evidences have consistently reported lower glutamate (Glu) levels in various brain regions, including the medial prefrontal cortex (mPFC), in chronic schizophrenia but findings in the early (EP) or in the prodromal phase of the disorder are equivocal. Although regular cannabis use has been associated with an increased risk of subsequent psychosis and with a perturbed Glu signalling, to date, the critical question of whether or not Glu abnormalities exist in EP and are related to cannabis use remains unanswered. Magnetic resonance spectroscopy was used to measure [GlumPFC] of 35 EP subjects (18 of whom were regular cannabis users) and 33 healthy controls (HC). For correlative analysis, neuropsychological performances were scored by a comprehensive cognitive battery. [GlumPFC] was lower in EP users comparing to both HC and EP non-users (P = 0.001 and P = 0.01, respectively), while no differences were observed between HC and EP non-users. In EP users Glu declined with age (r = −0.46; P = 0.04) but this relationship was not observed in non-users. Among neuropsychological profiles, working memory was the only domain that differentiates patients depending on their cannabis use, with users having poorer performances. In summary, our research revealed that cannabis use in EP is associated with Glu decreased levels, which are normally not seen in the early phase of the disorder. This finding is in line with previous 1H-MRS studies in cannabis users without a psychotic disorder and sheds light for the role of cannabis use in the progression of the disease.Disclosure of interestThe authors have not supplied their declaration of competing interest.

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Inferring cortical function in the mouse visual system through large-scale systems neuroscience

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1512901113 ◽

2016 ◽

Vol 113 (27) ◽

pp. 7337-7344 ◽

Cited By ~ 48

Author(s):

Michael Hawrylycz ◽

Costas Anastassiou ◽

Anton Arkhipov ◽

Jim Berg ◽

Michael Buice ◽

...

Keyword(s):

Cortical Neurons ◽

Large Scale ◽

Model Organism ◽

Building Blocks ◽

Mammalian Brain ◽

Cortical Function ◽

Scientific Mission ◽

Large Populations ◽

Cell Type Specific ◽

And Behavior

The scientific mission of the Project MindScope is to understand neocortex, the part of the mammalian brain that gives rise to perception, memory, intelligence, and consciousness. We seek to quantitatively evaluate the hypothesis that neocortex is a relatively homogeneous tissue, with smaller functional modules that perform a common computational function replicated across regions. We here focus on the mouse as a mammalian model organism with genetics, physiology, and behavior that can be readily studied and manipulated in the laboratory. We seek to describe the operation of cortical circuitry at the computational level by comprehensively cataloging and characterizing its cellular building blocks along with their dynamics and their cell type-specific connectivities. The project is also building large-scale experimental platforms (i.e., brain observatories) to record the activity of large populations of cortical neurons in behaving mice subject to visual stimuli. A primary goal is to understand the series of operations from visual input in the retina to behavior by observing and modeling the physical transformations of signals in the corticothalamic system. We here focus on the contribution that computer modeling and theory make to this long-term effort.

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Function and Plasticity of Electrical Synapses in the Mammalian Brain: Role of Non-Junctional Mechanisms

10.20944/preprints202112.0384.v1 ◽

2021 ◽

Author(s):

Sebastian Curti ◽

Federico Davoine ◽

Antonella Dapino

Keyword(s):

Molecular Mechanisms ◽

Mammalian Brain ◽

Synaptic Membrane ◽

Electrical Transmission ◽

Electrical Synapses ◽

Electrophysiological Properties ◽

Voltage Dependent ◽

Theoretical Evidence ◽

Circuit Function

Electrical transmission between neurons is largely mediated by gap junctions. These junctions allow the direct flow of electric current between neurons, and in mammals are mostly composed of the protein connexin (Cx)36. Circuits of electrically coupled neurons are widespread in these animals, plus, experimental and theoretical evidence supports the notion that, beyond synchronicity, these circuits are able to perform sophisticated operations like lateral excitation and inhibition, noise reduction, as well as the ability to selectively respond upon coincident excitatory inputs. Although once considered stereotyped and unmodifiable, we now know that electrical synapses are subject to modulation and, by reconfiguring neural circuits, these modulations can alter relevant operations. The strength of electrical synapses depends on gap junction conductance, as well as on its functional interaction with the electrophysiological properties of coupled neurons. In particular, voltage dependent channels of the non-synaptic membrane critically determine the efficacy of transmission at these contacts. Consistently, modulatory actions on these channels have been shown to represent relevant mechanisms of plasticity of electrical synaptic transmission. Here we review recent evidence on the regulation of electrical synapses of mammals, the underlying molecular mechanisms, and the possible ways in which they affect circuit function.

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Frequency and Intensity of Premonitory Urges to tic in Tourette Syndrome is associated with SMA GABA+ levels

10.31234/osf.io/j8uwc ◽

2021 ◽

Author(s):

Jason He ◽

Mark Mikkelsen ◽

David Huddleston ◽

Deana Crocetti ◽

Kim Cecil ◽

...

Keyword(s):

Tourette Syndrome ◽

Insular Cortex ◽

Brain Regions ◽

Resonance Spectroscopy ◽

Typically Developing ◽

Gabaergic Neurotransmission ◽

Primary Sensorimotor Cortex ◽

Tic Severity ◽

The Right

Background. Individuals with Tourette syndrome (TS) often report that they express tics as a means of alleviating the experience of unpleasant sensations. These sensations are perceived as an urge to act and are referred to as premonitory urges. Premonitory urges have been the focus of recent efforts to develop interventions to reduce tic expression in those with TS. Increasing evidence points to the role of both structural and functional alterations of prefrontal and limbic brain regions regarding the experience of premonitory urges to tic in TS. This study examined the contribution of brain GABA and glutamate levels of the right primary sensorimotor cortex (SM1), supplementary motor area (SMA), and insular cortex (insula) to tic and urge severity in children with TS.Methods. Edited magnetic resonance spectroscopy was used to assess GABA+ (GABA + macromolecules) and Glx (glutamate + glutamine) of the right SM1, SMA and insula in 68 children with TS (MAge = 10.59, SDAge = 1.33) and 41 typically developing controls (MAge = 10.26, SDAge = 2.21). We first compared GABA+ and Glx levels of these brain regions between groups. We then explored the association between regional GABA+ and Glx levels with urge and tic severity. Results. GABA+ and Glx of the right SM1, SMA and insula were comparable between the children with TS and typically developing controls. In children with TS, lower levels of SMA GABA+ was associated with more severe and more frequent premonitory urges. Neither GABA+ nor Glx levels were associated with tic severity. Conclusions. These results broadly support the role of GABAergic neurotransmission within the SMA in the experience of premonitory urges in children with TS.

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Migratory state is not associated with differences in neural glucocorticoid or mineralocorticoid receptor expression in pine siskins

Animal Migration ◽

10.1515/ami-2019-0001 ◽

2019 ◽

Vol 6 (1) ◽

pp. 19-27 ◽

Cited By ~ 1

Author(s):

Heather E. Watts ◽

Jeffrey L. Rittenhouse ◽

Kendra B. Sewall ◽

J. Michael Bowers

Keyword(s):

Mineralocorticoid Receptor ◽

Migratory Birds ◽

Endocrine System ◽

Brain Regions ◽

Receptor Expression ◽

Migratory Restlessness ◽

Potential Mechanism ◽

Glucocorticoid Signaling ◽

And Behavior

Abstract Although the endocrine system likely plays an important role in orchestrating the transition to a migratory state, the specific mechanisms by which this occurs remain poorly understood. Changes in glucocorticoid signaling are one proposed mechanism that may be important in migratory transitions. Although previous work has focused on the role of changes in circulating glucocorticoids, another potential mechanism is changes in the expression of its cognate receptors. Here, we test this hypothesis by comparing mRNA expression of the genes for the mineralocorticoid receptor (MR) and glucocorticoid receptor (GR) in two brain regions implicated in the regulation of migratory behavior (the hippocampus and hypothalamus) in pine siskins (Spinus pinus) sampled before or after the transition to a spring nomadic migratory state. Compared to pre-migratory birds, migratory birds had body conditions more indicative of physiological preparations for migration (e.g., larger body mass), and greater levels of nocturnal migratory restlessness. However, we found no differences between pre-migratory and migratory birds in the expression of GR or MR mRNA in either the hippocampus or hypothalamus. Thus, differences in expression of receptors for glucocorticoids do not appear to underly the observed differences in physiology and behavior across a migratory transition. Taken together with previous results showing no change in circulating corticosterone levels during this transition, our findings provide no evidence for a role of glucocorticoid signaling in the spring migratory transition of this species.

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Function and Plasticity of Electrical Synapses in the Mammalian Brain: Role of Non-Junctional Mechanisms

Biology ◽

10.3390/biology11010081 ◽

2022 ◽

Vol 11 (1) ◽

pp. 81

Author(s):

Sebastian Curti ◽

Federico Davoine ◽

Antonella Dapino

Keyword(s):

Molecular Mechanisms ◽

Mammalian Brain ◽

Synaptic Membrane ◽

Electrical Transmission ◽

Electrical Synapses ◽

Electrophysiological Properties ◽

Theoretical Evidence ◽

Circuit Function ◽

Lateral Excitation

Electrical transmission between neurons is largely mediated by gap junctions. These junctions allow the direct flow of electric current between neurons, and in mammals, they are mostly composed of the protein connexin36. Circuits of electrically coupled neurons are widespread in these animals. Plus, experimental and theoretical evidence supports the notion that, beyond synchronicity, these circuits are able to perform sophisticated operations such as lateral excitation and inhibition, noise reduction, as well as the ability to selectively respond upon coincident excitatory inputs. Although once considered stereotyped and unmodifiable, we now know that electrical synapses are subject to modulation and, by reconfiguring neural circuits, these modulations can alter relevant operations. The strength of electrical synapses depends on the gap junction resistance, as well as on its functional interaction with the electrophysiological properties of coupled neurons. In particular, voltage and ligand gated channels of the non-synaptic membrane critically determine the efficacy of transmission at these contacts. Consistently, modulatory actions on these channels have been shown to represent relevant mechanisms of plasticity of electrical synaptic transmission. Here, we review recent evidence on the regulation of electrical synapses of mammals, the underlying molecular mechanisms, and the possible ways in which they affect circuit function.

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