Deletion of BDNF in Pax2 Lineage-Derived Interneuron Precursors in the Hindbrain Hampers the Proportion of Excitation/Inhibition, Learning, and Behavior

Numerous studies indicate that deficits in the proper integration or migration of specific GABAergic precursor cells from the subpallium to the cortex can lead to severe cognitive dysfunctions and neurodevelopmental pathogenesis linked to intellectual disabilities. A different set of GABAergic precursors cells that express Pax2 migrate to hindbrain regions, targeting, for example auditory or somatosensory brainstem regions. We demonstrate that the absence of BDNF in Pax2-lineage descendants of BdnfPax2KOs causes severe cognitive disabilities. In BdnfPax2KOs, a normal number of parvalbumin-positive interneurons (PV-INs) was found in the auditory cortex (AC) and hippocampal regions, which went hand in hand with reduced PV-labeling in neuropil domains and elevated activity-regulated cytoskeleton-associated protein (Arc/Arg3.1; here: Arc) levels in pyramidal neurons in these same regions. This immaturity in the inhibitory/excitatory balance of the AC and hippocampus was accompanied by elevated LTP, reduced (sound-induced) LTP/LTD adjustment, impaired learning, elevated anxiety, and deficits in social behavior, overall representing an autistic-like phenotype. Reduced tonic inhibitory strength and elevated spontaneous firing rates in dorsal cochlear nucleus (DCN) brainstem neurons in otherwise nearly normal hearing BdnfPax2KOs suggests that diminished fine-grained auditory-specific brainstem activity has hampered activity-driven integration of inhibitory networks of the AC in functional (hippocampal) circuits. This leads to an inability to scale hippocampal post-synapses during LTP/LTD plasticity. BDNF in Pax2-lineage descendants in lower brain regions should thus be considered as a novel candidate for contributing to the development of brain disorders, including autism.

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Spine impairment in mice high-expressing neuregulin 1 due to LIMK1 activation

Cell Death and Disease ◽

10.1038/s41419-021-03687-8 ◽

2021 ◽

Vol 12 (4) ◽

Author(s):

Peng Chen ◽

Hongyang Jing ◽

Mingtao Xiong ◽

Qian Zhang ◽

Dong Lin ◽

...

Keyword(s):

Neural Development ◽

Protein Level ◽

Brain Regions ◽

Postmortem Brain ◽

Pathophysiological Mechanism ◽

Brain Disorders ◽

Spine Density ◽

Genes Encoding ◽

High Level ◽

And Function

AbstractThe genes encoding for neuregulin1 (NRG1), a growth factor, and its receptor ErbB4 are both risk factors of major depression disorder and schizophrenia (SZ). They have been implicated in neural development and synaptic plasticity. However, exactly how NRG1 variations lead to SZ remains unclear. Indeed, NRG1 levels are increased in postmortem brain tissues of patients with brain disorders. Here, we studied the effects of high-level NRG1 on dendritic spine development and function. We showed that spine density in the prefrontal cortex and hippocampus was reduced in mice (ctoNrg1) that overexpressed NRG1 in neurons. The frequency of miniature excitatory postsynaptic currents (mEPSCs) was reduced in both brain regions of ctoNrg1 mice. High expression of NRG1 activated LIMK1 and increased cofilin phosphorylation in postsynaptic densities. Spine reduction was attenuated by inhibiting LIMK1 or blocking the NRG1–LIMK1 interaction, or by restoring NRG1 protein level. These results indicate that a normal NRG1 protein level is necessary for spine homeostasis and suggest a pathophysiological mechanism of abnormal spines in relevant brain disorders.

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Alterations of Expression of the Serotonin 5-HT4 Receptor in Brain Disorders

International Journal of Molecular Sciences ◽

10.3390/ijms19113581 ◽

2018 ◽

Vol 19 (11) ◽

pp. 3581 ◽

Cited By ~ 16

Author(s):

Heike Rebholz ◽

Eitan Friedman ◽

Julia Castello

Keyword(s):

Executive Function ◽

Food Intake ◽

Serotonin Receptor ◽

Current Knowledge ◽

Memory Loss ◽

Brain Regions ◽

Brain Disorders ◽

Protein Levels ◽

Preclinical Animal Models ◽

Mood Depression

The serotonin 4 receptor, 5-HT4R, represents one of seven different serotonin receptor families and is implicated in a variety of physiological functions and their pathophysiological variants, such as mood and depression or anxiety, food intake and obesity or anorexia, or memory and memory loss in Alzheimer’s disease. Its central nervous system expression pattern in the forebrain, in particular in caudate putamen, the hippocampus and to lesser extent in the cortex, predispose it for a role in executive function and reward-related actions. In rodents, regional overexpression or knockdown in the prefrontal cortex or the nucleus accumbens of 5-HT4R was shown to impact mood and depression-like phenotypes, food intake and hypophagia; however, whether expression changes are causally involved in the etiology of such disorders is not clear. In this context, more data are emerging, especially based on PET technology and the use of ligand tracers that demonstrate altered 5-HT4R expression in brain disorders in humans, confirming data stemming from post-mortem tissue and preclinical animal models. In this review, we would like to present the current knowledge of 5-HT4R expression in brain regions relevant to mood/depression, reward and executive function with a focus on 5-HT4R expression changes in brain disorders or caused by drug treatment, at both the transcript and protein levels.

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Preferential cholinergic excitation of corticopontine neurons

10.1101/182667 ◽

2017 ◽

Cited By ~ 1

Author(s):

Arielle L. Baker ◽

Ryan J. O’Toole ◽

Allan T. Gulledge

Keyword(s):

Pyramidal Neurons ◽

Projection Neurons ◽

Triggered Release ◽

Calcium Dependent ◽

M Current ◽

Cation Conductance ◽

Specific Selectivity ◽

Ionic Mechanisms ◽

Excitatory Responses ◽

And Behavior

AbstractPyramidal neurons in layer 5 of the neocortex comprise two broad classes of projection neurons: corticofugal neurons, including corticopontine (CPn) neurons, and intratelencephalic neurons, including commissural/callosal (COM) neurons. These non-overlapping neuron subpopulations represent discrete cortical output channels contributing to perception, decision making, and behavior. CPn and COM neurons have distinct morphological and physiological characteristics, and divergent responses to modulatory transmitters such as serotonin and acetylcholine (ACh). To better understand how ACh regulates cortical output, in slices of mouse prefrontal cortex (PFC) we compared the responsivity of CPn and COM neurons to transient exposure to exogenous or endogenous ACh. In both neuron subtypes, exogenous ACh generated qualitatively similar biphasic responses in which brief hyperpolarization was followed by longer-lasting enhancement of excitability. However, cholinergic inhibition was more pronounced in COM neurons, while excitatory responses were larger and longer lasting in CPn neurons. Similarly, optically triggered release of endogenous ACh from cholinergic terminals preferentially and persistently (for ~40 s) enhanced the excitability of CPn neurons, but had little impact on COM neurons. Cholinergic excitation of CPn neurons involved at least three distinct ionic mechanisms: activation of a calcium-sensitive but calcium-permeable nonspecific cation conductance, suppression of Kv7 channels (the “M-current”), and activation of the calcium-dependent nonspecific cation conductance underlying afterdepolarizations. Our results demonstrate projection-specific selectivity in cholinergic signaling in the PFC, and suggest that transient release of ACh during behavior will preferentially promote corticofugal output.

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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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Features Of Hippocampal Astrocytic Domains And Their Spatial Relation To Excitatory And Inhibitory Neurons

10.1101/2020.05.25.114348 ◽

2020 ◽

Author(s):

Ron Refaeli ◽

Adi Doron ◽

Aviya Benmelech-Chovav ◽

Maya Groysman ◽

Tirzah Kreisel ◽

...

Keyword(s):

Spatial Distribution ◽

Pyramidal Neurons ◽

Spatial Relation ◽

Design Principles ◽

Inhibitory Neurons ◽

Computational Tools ◽

Close Proximity ◽

Somatostatin Neurons ◽

And Behavior ◽

Elaborate Structure

SUMMARYThe mounting evidence for the involvement of astrocytes in neuronal circuits function and behavior stands in stark contrast to the lack of detailed anatomical description of these cells and the neurons in their domains. To fill this void, we imaged >30,000 astrocytes in cleared hippocampi, and employed converging genetic, histological and computational tools to determine the elaborate structure, distribution and neuronal content of astrocytic domains. First, we characterized the spatial distribution of >19,000 astrocytes across CA1 lamina, and analyzed the detailed morphology of thousands of reconstructed domains. We then determined the excitatory content of CA1 astrocytes, averaging above 13 pyramidal neurons per domain and increasing towards CA1 midline. Finally, we discovered that somatostatin neurons are found in close proximity to astrocytes, compared to parvalbumin and VIP inhibitory neurons. This resource expands our understanding of fundamental hippocampal design principles, and provides the first quantitative foundation for neuron-astrocyte interactions in this region.

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Top-down coordination of local cortical state during selective attention

10.1101/2020.03.26.009365 ◽

2020 ◽

Cited By ~ 1

Author(s):

Jochem van Kempen ◽

Marc A. Gieselmann ◽

Michael Boyd ◽

Nicholas A. Steinmetz ◽

Tirin Moore ◽

...

Keyword(s):

Selective Attention ◽

Cortical Excitability ◽

Brain Regions ◽

Global Changes ◽

Top Down ◽

Visual Hierarchy ◽

Tightly Coupled ◽

State Coordination ◽

And Behavior ◽

Spontaneous Fluctuations

AbstractSpontaneous fluctuations in cortical excitability influence sensory processing and behavior. These fluctuations, long known to reflect global changes in cortical state, were recently found to be modulated locally within a retinotopic map during spatially selective attention. We found that periods of vigorous (On) and faint (Off) spiking activity, the signature of cortical state fluctuations, were coordinated across brain areas along the visual hierarchy and tightly coupled to their retinotopic alignment. During top-down attention, this interareal coordination was enhanced and progressed along the reverse cortical hierarchy. The extent of local state coordination between areas was predictive of behavioral performance. Our results show that cortical state dynamics are shared across brain regions, modulated by cognitive demands and relevant for behavior.One Sentence SummaryInterareal coordination of local cortical state is retinotopically precise and progresses in a reverse hierarchical manner during selective attention.

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Slow Cortical Waves via Cyclicity

10.1101/2021.05.16.444387 ◽

2021 ◽

Author(s):

Ivan Abraham ◽

Bahar Shahsavarani ◽

Ben Zimmerman ◽

Fatima Husain ◽

yuliy baryshnikov

Keyword(s):

Time Series ◽

Dynamic Structure ◽

Resting State Fmri ◽

Brain Regions ◽

Fine Grained ◽

Human Connectome Project ◽

Fmri Time Series ◽

The Brain ◽

Cortical Waves ◽

Temporal Ordering

Fine-grained information about dynamic structure of cortical networks is crucial in unpacking brain function. Here,we introduced a novel analytical method to characterize the dynamic interaction between distant brain regions,based on cyclicity analysis, and applied it to data from the Human Connectome Project. Resting-state fMRI time series are aperiodic and, hence, lack a base frequency. Cyclicity analysis, which is time-reparametrization invariant, is effective in recovering dynamic temporal ordering of such time series along a circular trajectory without assuming any time scale. Our analysis detected the propagation of slow cortical waves across thebrain with consistent shifts in lead-lag relationships between specific brain regions. We also observed short bursts of strong temporal ordering that dominated overall lead-lag relationships between pairs of regions in the brain, which were modulated by tasks. Our results suggest the possible role played by slow waves of ordered information between brain regions that underlie emergent cognitive function.

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Developmental Regulation of Basket Interneuron Synapses and Behavior through NCAM in Mouse Prefrontal Cortex

Cerebral Cortex ◽

10.1093/cercor/bhaa074 ◽

2020 ◽

Vol 30 (8) ◽

pp. 4689-4707

Author(s):

Chelsea S Sullivan ◽

Vishwa Mohan ◽

Paul B Manis ◽

Sheryl S Moy ◽

Young Truong ◽

...

Keyword(s):

Prefrontal Cortex ◽

Pyramidal Neurons ◽

Developmental Regulation ◽

Brain Slices ◽

Pyramidal Cells ◽

Electrophysiological Recording ◽

Network Function ◽

Growth Cone Collapse ◽

Layer 2 ◽

And Behavior

Abstract Parvalbumin (PV)-expressing basket interneurons in the prefrontal cortex (PFC) regulate pyramidal cell firing, synchrony, and network oscillations. Yet, it is unclear how their perisomatic inputs to pyramidal neurons are integrated into neural circuitry and adjusted postnatally. Neural cell adhesion molecule NCAM is expressed in a variety of cells in the PFC and cooperates with EphrinA/EphAs to regulate inhibitory synapse density. Here, analysis of a novel parvalbumin (PV)-Cre: NCAM F/F mouse mutant revealed that NCAM functions presynaptically in PV+ basket interneurons to regulate postnatal elimination of perisomatic synapses. Mutant mice exhibited an increased density of PV+ perisomatic puncta in PFC layer 2/3, while live imaging in mutant brain slices revealed fewer puncta that were dynamically eliminated. Furthermore, EphrinA5-induced growth cone collapse in PV+ interneurons in culture depended on NCAM expression. Electrophysiological recording from layer 2/3 pyramidal cells in mutant PFC slices showed a slower rise time of inhibitory synaptic currents. PV-Cre: NCAM F/F mice exhibited impairments in working memory and social behavior that may be impacted by altered PFC circuitry. These findings suggest that the density of perisomatic synapses of PV+ basket interneurons is regulated postnatally by NCAM, likely through EphrinA-dependent elimination, which is important for appropriate PFC network function and behavior.

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Astrocyte dysfunction increases cortical dendritic excitability and promotes cranial pain in familial migraine

Science Advances ◽

10.1126/sciadv.aaz1584 ◽

2020 ◽

Vol 6 (23) ◽

pp. eaaz1584 ◽

Cited By ~ 3

Author(s):

Jennifer Romanos ◽

Dietmar Benke ◽

Daniela Pietrobon ◽

Hanns Ulrich Zeilhofer ◽

Mirko Santello

Keyword(s):

Mouse Model ◽

Pyramidal Neurons ◽

Glutamate Uptake ◽

Cingulate Cortex ◽

Familial Hemiplegic Migraine ◽

Strong Impact ◽

Two Photon Microscopy ◽

Genetic Mouse Model ◽

Cortical Physiology ◽

And Behavior

Astrocytes are essential contributors to neuronal function. As a consequence, disturbed astrocyte-neuron interactions are involved in the pathophysiology of several neurological disorders, with a strong impact on brain circuits and behavior. Here, we describe altered cortical physiology in a genetic mouse model of familial hemiplegic migraine type 2 (FHM2), with reduced expression of astrocytic Na+,K+-ATPases. We used whole-cell electrophysiology, two-photon microscopy, and astrocyte gene rescue to demonstrate that an impairment in astrocytic glutamate uptake promotes NMDA spike generation in dendrites of cingulate cortex pyramidal neurons and enhances output firing of these neurons. Astrocyte compensation of the defective ATPase in the cingulate cortex rescued glutamate uptake, prevented abnormal NMDA spikes, and reduced sensitivity to cranial pain triggers. Together, our results demonstrate that impaired astrocyte function alters neuronal activity in the cingulate cortex and facilitates migraine-like cranial pain states in a mouse model of migraine.

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Brain Activity in Self- and Value-Related Regions in Response to Online Antismoking Messages Predicts Behavior Change

Journal of Media Psychology Theories Methods and Applications ◽

10.1027/1864-1105/a000146 ◽

2015 ◽

Vol 27 (3) ◽

pp. 93-109 ◽

Cited By ~ 35

Author(s):

Nicole Cooper ◽

Steve Tompson ◽

Matthew Brook O’Donnell ◽

B. Falk Emily

Keyword(s):

Behavior Change ◽

Risk Perceptions ◽

Brain Activity ◽

Smoking Behavior ◽

Mechanistic Explanation ◽

Health Behavior Change ◽

Brain Regions ◽

Self Report ◽

Traditional Theory ◽

And Behavior

Abstract. In this study, we combined approaches from media psychology and neuroscience to ask whether brain activity in response to online antismoking messages can predict smoking behavior change. In particular, we examined activity in subregions of the medial prefrontal cortex linked to self- and value-related processing, to test whether these neurocognitive processes play a role in message-consistent behavior change. We observed significant relationships between activity in both brain regions of interest and behavior change (such that higher activity predicted a larger reduction in smoking). Furthermore, activity in these brain regions predicted variance independent of traditional, theory-driven self-report metrics such as intention, self-efficacy, and risk perceptions. We propose that valuation is an additional cognitive process that should be investigated further as we search for a mechanistic explanation of the relationship between brain activity and media effects relevant to health behavior change.

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