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1.
Mol Psychiatry ; 2022 May 12.
Artigo em Inglês | MEDLINE | ID: mdl-35551246

RESUMO

Generalization, the process of applying knowledge acquired in one context to other contexts, often drives the expression of similar behaviors in related situations. At the cellular level, generalization is thought to depend on the activity of overlapping neurons that represent shared features between contexts (general representations). Using contextual fear conditioning in mice, we demonstrate that generalization can also occur in response to stress and result from reactivation of specific, rather than general context representations. We found that generalization emerges during memory retrieval, along with stress-induced abnormalities of septohippocampal oscillatory activity and acetylcholine release, which are typically found in negative affective states. In hippocampal neurons that represent aversive memories and drive generalization, cholinergic septohippocampal afferents contributed to a unique reactivation pattern of cFos, Npas4, and repressor element-1 silencing transcription factor (REST). Together, these findings suggest that generalization can be triggered by perceptually dissimilar but valence-congruent memories of specific aversive experiences. Through promoting the reactivation of such memories and their interference with ongoing behavior, abnormal cholinergic signaling could underlie maladaptive cognitive and behavioral generalization linked to negative affective states.

3.
Bioelectrochemistry ; 145: 108088, 2022 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-35189558

RESUMO

The problem of wastewater has long been ubiquitous and has great consequences for the environment and its inhabitants. Microbial fuel cells (MFCs) have enormous potential for the treatment of wastewaters polluted with azo dyes. The amount of energy that can be produced from a single-chamber MFC is sufficient to perform decolorization and degradation of such dyes, which are widely used in the textile industry. This study on the azo dye, reactive black 5 (RB5), provides an alternative method through three parallel-connected MFCs to obtain electricity that directly serves for the dye's electrochemical degradation. We examined degradation followed by decolorization of RB5 using Fe and Pt electrodes, together with H2O2, to achieve the electro-Fenton process. The amount of voltage produced (295 mV), the current density (276 mA m-3) and the power density (50 mW m-3) were sufficient to degrade 25 mg L-1 RB5 dye with 0.5 mM H2O2 in just 2 h. The dye degradation mechanism was investigated using UV-VIS, FT-IR and HPLC-MS/MS. The ecotoxicity of the degradation products was assessed using a bacterial model, Aliivibrio fischeri. These tests showed that there was successful degradation of the dye to products whose toxicity is less than that of RB5.

4.
Handb Clin Neurol ; 184: 481-495, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35034756

RESUMO

To adapt to the sustained demands of chronic stress, discrete brain circuits undergo structural and functional changes often resulting in anxiety disorders. In some individuals, anxiety disorders precede the development of motor symptoms of Parkinson's disease (PD) caused by degeneration of neurons in the substantia nigra (SN). Here, we present a circuit framework for probing a causal link between chronic stress, anxiety, and PD, which postulates a central role of abnormal neuromodulation of the SN's axon initial segment by brainstem inputs. It is grounded in findings demonstrating that the earliest PD pathologies occur in the stress-responsive, emotion regulation network of the brainstem, which provides the SN with dense aminergic and cholinergic innervation. SN's axon initial segment (AIS) has unique features that support the sustained and bidirectional propagation of activity in response to synaptic inputs. It is therefore, especially sensitive to circuit-mediated stress-induced imbalance of neuromodulation, and thus a plausible initiating site of neurodegeneration. This could explain why, although secondary to pathophysiologies in other brainstem nuclei, SN degeneration is the most extensive. Consequently, the cardinal symptom of PD, severe motor deficits, arise from degeneration of the nigrostriatal pathway rather than other brainstem nuclei. Understanding when and how circuit dysfunctions underlying anxiety can progress to neurodegeneration, raises the prospect of timed interventions for reversing, or at least impeding, the early pathophysiologies that lead to PD and possibly other neurodegenerative disorders.


Assuntos
Segmento Inicial do Axônio , Doença de Parkinson , Ansiedade , Transtornos de Ansiedade , Humanos , Substância Negra
5.
Neuropsychopharmacology ; 47(2): 516-523, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34493828

RESUMO

Memories of negative experiences exert important control of behavior in the face of actual or anticipated threat. Sometimes, however, this control extends to non-threatening situations, a phenomenon known as overgeneralization of negative memories. Overgeneralization is a reliable cognitive phenotype of major depressive disorder, generalized anxiety disorder, and post-traumatic stress disorder. We therefore sought to develop an animal model to study stress-induced generalization of negative memories (SIG) and determine its dependence on the episodic-like memory circuit. We found that male and female mice, which were trained to differentiate a threatening from neutral context, exhibited robust SIG in response to subsequent social stress. Using chemogenetic circuit manipulations during memory retrieval, we demonstrated that both excitatory afferents to the dorsal hippocampus (DH) from the ventral tegmental area (VTA), and excitatory efferents from the DH to the retrosplenial cortex (RSC) contribute to SIG. Based on the known roles of these projections, we suggest that (1) by targeting subcortical VTA circuits that provide valence signals to the DH, stress prioritizes the retrieval of negative over neutral memories, and (2) by forwarding such information to the RSC, stress engages cortical mechanisms that support the retrieval of general relative to specific memory features. Altogether, these results suggest that various components of the extended hippocampal circuit can serve as treatment targets for memory overgeneralization.


Assuntos
Transtorno Depressivo Maior , Medo , Animais , Cognição , Medo/fisiologia , Feminino , Hipocampo/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL
6.
Behav Brain Res ; 417: 113625, 2022 01 24.
Artigo em Inglês | MEDLINE | ID: mdl-34637854

RESUMO

Inflammation plays a key role in the pathogenesis of the major depressive disorder. Namely, neuroinflammation can induce the production of neuroactive metabolites that interfere with N-methyl-D-aspartate receptors (NMDAR)-mediated glutamatergic neurotransmission and contribute to depressive-like behaviour. On the other hand, mammalian target of rapamycin (mTOR) activity with synaptogenic effects is the main mediator of antidepressant effects of several potent NMDAR antagonists. In this study, we investigated the specific role of GluN2A subunits of NMDAR on the activity of mTOR signaling and behaviour in lipopolysaccharide (LPS)-induces model of depression. The results showed that mice lacking GluN2A subunit did not display depressive-like behavior after the immune challenge, opposite to LPS-treated wild-type mice. Specifically, in GluN2A knockout mice, we estimated the activity of the mTOR pathway in the hippocampus and prefrontal cortex (PFC) by measuring synaptic levels of upstream regulators (p-Akt, p-ERK, and p-GSK3ß) and downstream effectors (p-mTOR, and p-p70S6K) of mTOR activity. In addition, we assessed the changes in the levels of two important synaptic markers, GluA1 and PSD-95. Contrary to downregulated mTOR signaling and decreased synaptic markers in LPS-treated wild-type animals, the resilience of GluN2A KO mice to depressive-like behaviour was paralleled with sustained mTOR signaling activity synaptic stability in hippocampus and PFC. Finally, we disclosed that resistance of GluN2A knockouts to LPS-induced depressive-like behavior was ERK-dependent. These findings demonstrate that GluN2A-ERK-mTOR signaling is a vulnerability factor of inflammation-related depressive behaviour, making this signaling pathway the promising target for developing novel antidepressants.


Assuntos
Depressão/metabolismo , Proteína 4 Homóloga a Disks-Large/metabolismo , Hipocampo/metabolismo , Lipopolissacarídeos/farmacologia , Receptores de N-Metil-D-Aspartato/metabolismo , Animais , Depressão/induzido quimicamente , Masculino , Camundongos , Camundongos Knockout , Córtex Pré-Frontal/metabolismo , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR
7.
STAR Protoc ; 2(4): 100931, 2021 12 17.
Artigo em Inglês | MEDLINE | ID: mdl-34778848

RESUMO

Perineuronal nets (PNNs) are emerging as critical regulators of memory-related neuronal processes. However, their exact contribution depends on type of memory, consolidation stage, or brain region, and remains to be fully investigated. We describe here a protocol to evaluate the importance of PNNs in the dorsal hippocampus in different stages of aversive memories using a mouse model. The protocol provides detailed instructions for surgical implantation of hippocampal cannulas, drug infusion, contextual fear conditioning procedures, and immunohistochemistry for PNN visualization. For complete details on the use and execution of this protocol, please refer to Jovasevic et al. (2021).


Assuntos
Medo/fisiologia , Hipocampo , Memória/fisiologia , Rede Nervosa , Animais , Comportamento Animal/fisiologia , Condicionamento Clássico , Hipocampo/química , Hipocampo/citologia , Hipocampo/fisiologia , Imuno-Histoquímica , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Rede Nervosa/citologia , Rede Nervosa/fisiologia
8.
Cell Rep Med ; 2(5): 100282, 2021 05 18.
Artigo em Inglês | MEDLINE | ID: mdl-34095884

RESUMO

Vanderplow et al.1 report decreased PFC Akt-mTOR signaling in males with bipolar disorder (BD) without psychosis compared with those with psychosis, possibly related to cognitive deficits. Understanding how cognition differs between these BD subtypes clinically and biologically remains a challenge.


Assuntos
Transtorno Bipolar , Transtornos Cognitivos , Transtornos Psicóticos , Cognição , Humanos , Masculino , Serina-Treonina Quinases TOR
9.
iScience ; 24(6): 102617, 2021 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-34142063

RESUMO

It is well established that the formation of episodic memories requires multiple hippocampal mechanisms operating on different time scales. Early mechanisms of memory formation (synaptic consolidation) have been extensively characterized. However, delayed mechanisms, which maintain hippocampal activity as memories stabilize in cortical circuits, are not well understood. Here we demonstrate that contrary to the transient expression of early- and delayed-response genes, the expression of cytoskeleton- and extracellular matrix-associated genes remains dynamic even at remote time points. The most profound expression changes clustered around primary cilium-associated and collagen genes. These genes most likely contribute to memory by stabilizing perineuronal nets in the dorsohippocampal CA1 subfield, as revealed by targeted disruptions of the primary cilium or perineuronal nets. The findings show that nonsynaptic, primary cilium-mediated mechanisms are required for the persistence of context memory.

10.
Pain ; 162(12): 2865-2880, 2021 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-34160168

RESUMO

ABSTRACT: Accumulating evidence suggests hippocampal impairment under the chronic pain phenotype. However, it is unknown whether neuropathic behaviors are related to dysfunction of the hippocampal circuitry. Here, we enhanced hippocampal activity by pharmacological, optogenetic, and chemogenetic techniques to determine hippocampal influence on neuropathic pain behaviors. We found that excitation of the dorsal (DH), but not the ventral (VH) hippocampus induces analgesia in 2 rodent models of neuropathic pain (SNI and SNL) and in rats and mice. Optogenetic and pharmacological manipulations of DH neurons demonstrated that DH-induced analgesia was mediated by N-Methyl-D-aspartate and µ-opioid receptors. In addition to analgesia, optogenetic stimulation of the DH in SNI mice also resulted in enhanced real-time conditioned place preference for the chamber where the DH was activated, a finding consistent with pain relief. Similar manipulations in the VH were ineffective. Using chemo-functional magnetic resonance imaging (fMRI), where awake resting-state fMRI was combined with viral vector-mediated chemogenetic activation (PSAM/PSEM89s) of DH neurons, we demonstrated changes of functional connectivity between the DH and thalamus and somatosensory regions that tracked the extent of relief from tactile allodynia. Moreover, we examined hippocampal functional connectivity in humans and observe differential reorganization of its anterior and posterior subdivisions between subacute and chronic back pain. Altogether, these results imply that downregulation of the DH circuitry during chronic neuropathic pain aggravates pain-related behaviors. Conversely, activation of the DH reverses pain-related behaviors through local excitatory and opioidergic mechanisms affecting DH functional connectivity. Thus, this study exhibits a novel causal role for the DH but not the VH in controlling neuropathic pain-related behaviors.


Assuntos
Neuralgia , Roedores , Animais , Hipocampo/diagnóstico por imagem , Camundongos , Neuralgia/diagnóstico por imagem , Neurônios , Ratos , Ratos Wistar
11.
Neurobiol Learn Mem ; 183: 107459, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34015441

RESUMO

Alcohol use disorder (AUD) frequently co-occurs with dissociative disorders and disorders with dissociative symptoms, suggesting a common neurobiological basis. It has been proposed that facilitated information processing under the influence of alcohol, resulting in the formation of dissociated memories, might be an important factor controlling alcohol use. Access to such memories is facilitated under the effect of alcohol, thus further reinforcing alcohol use. To interrogate possible mechanisms associated with these phenotypes, we used a mouse model of dissociative amnesia, combined with a high-alcohol preferring (HAP) model of AUD. Dissociated memory was induced by activation of hippocampal extrasynaptic GABA type A receptor delta subunits (GABAAR-δ), which control tonic inhibition and to which ethanol binds with high affinity. Increased ethanol preference was associated with increased propensity to form dissociated memories dependent on GABAAR-δ in the dorsal hippocampus (DH). Furthermore, the DH level of GABAAR-δ protein, but not mRNA, was increased in HAP mice, and was inversely correlated to the level of miR-365-3p, suggesting an miRNA-mediated post-transcriptional mechanism contributing to elevated GABAAR-δ. The observed changes of DH GABAAR-δ were associated with a severe reduction of excitatory projections stemming from GABAAR-δ-containing pyramidal neurons in the subiculum and terminating in the mammillary body. These results suggest that both molecular and circuit dysfunction involving hippocampal GABAAR-δ receptors might contribute to the co-occurrence of ethanol preference and dissociated information processing.


Assuntos
Amnésia/metabolismo , Depressores do Sistema Nervoso Central/administração & dosagem , Comportamento de Escolha/fisiologia , Etanol/administração & dosagem , Hipocampo/metabolismo , Memória/fisiologia , Células Piramidais/metabolismo , Receptores de GABA-A/metabolismo , Amnésia/fisiopatologia , Animais , Comportamento Animal/efeitos dos fármacos , Comportamento Animal/fisiologia , Comportamento de Escolha/efeitos dos fármacos , Condicionamento Clássico/efeitos dos fármacos , Condicionamento Clássico/fisiologia , Medo , Agonistas GABAérgicos/farmacologia , Hipocampo/fisiopatologia , Isoxazóis/farmacologia , Corpos Mamilares/metabolismo , Corpos Mamilares/fisiopatologia , Memória/efeitos dos fármacos , Memória Episódica , Camundongos , MicroRNAs/efeitos dos fármacos , MicroRNAs/metabolismo , Inibição Neural , Vias Neurais , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/fisiologia , Células Piramidais/efeitos dos fármacos , Células Piramidais/fisiologia , RNA Mensageiro/efeitos dos fármacos , RNA Mensageiro/metabolismo , Receptores de GABA-A/efeitos dos fármacos
13.
Brain Res Bull ; 171: 35-43, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33727088

RESUMO

Decades of neuroscience research in rodents have established an essential role of the hippocampus in the processing of episodic memories. Based on accumulating evidence of functional segregation in the hippocampus along the longitudinal axis, this role has been primarily ascribed to the dorsal hippocampus. More recent findings, however, demonstrate that functional segregation also occurs along transverse axis of the hippocampus, within the hippocampal subfields CA1, CA2, CA3, and the dentate gyrus (DG). Because the functional heterogeneity within CA1 has been addressed in several recent articles, here we discuss behavioral findings and putative mechanisms supporting generation of asymmetrical activity patterns along the transverse axis of DG and CA3. While transverse subnetworks appear to discretely contribute to the processing of spatial, non-spatial, temporal, and social components of episodic memories, integration of these components also occurs, especially in the CA3 subfield and possibly downstream, in the cortical targets of the hippocampus.


Assuntos
Hipocampo/fisiologia , Neurônios/fisiologia , Animais , Região CA1 Hipocampal/fisiologia , Região CA3 Hipocampal/fisiologia , Memória/fisiologia
14.
Transl Psychiatry ; 10(1): 428, 2020 12 12.
Artigo em Inglês | MEDLINE | ID: mdl-33311459

RESUMO

In susceptible individuals, memories of stressful experiences can give rise to debilitating socio-affective symptoms. This occurs even when the ability to retrieve such memories is limited, as seen in patients suffering from traumatic amnesia. We therefore hypothesized that the encoding, rather than retrieval, mechanisms of stress-related memories underlie their impact on social and emotional behavior. To test this hypothesis, we used combinations of stress-enhanced and state-dependent fear conditioning, which engage different encoding mechanisms for the formation of stress-related memories. We found that the encoding of stress-enhanced state-dependent memories robustly and sex specifically impairs sociability in male mice and disrupts the asymmetry of dentate gyrus (DG)/CA3 activity accompanying social interactions. These deficits were restored by chemogenetic inactivation of oxytocin receptor-positive interneurons localized in the hilus (Oxtr-HI), and by inactivation of dorsohippocampal efferents to the caudal lateral septum. Together, our data suggest that disrupted patterning of dorsohippocampal DG/CA3 activity underlies stress-induced sociability deficits, and that Oxtr-HI can be a cellular target for improving these deficits.


Assuntos
Interneurônios , Receptores de Ocitocina , Animais , Giro Denteado/metabolismo , Medo , Hipocampo/metabolismo , Humanos , Interneurônios/metabolismo , Masculino , Memória , Camundongos , Receptores de Ocitocina/genética , Receptores de Ocitocina/metabolismo
15.
Cell Rep ; 33(9): 108464, 2020 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-33264616

RESUMO

Store-operated Orai1 calcium channels function as highly Ca2+-selective ion channels and are broadly expressed in many tissues including the central nervous system, but their contributions to cognitive processing are largely unknown. Here, we report that many measures of synaptic, cellular, and behavioral models of learning are markedly attenuated in mice lacking Orai1 in forebrain excitatory neurons. Results with focal glutamate uncaging in hippocampal neurons support an essential role of Orai1 channels in amplifying NMDA-receptor-induced dendritic Ca2+ transients that drive activity-dependent spine morphogenesis and long-term potentiation at Schaffer collateral-CA1 synapses. Consistent with these signaling roles, mice lacking Orai1 in pyramidal neurons (but not interneurons) exhibit striking deficits in working and associative memory tasks. These findings identify Orai1 channels as essential regulators of dendritic spine Ca2+ signaling, synaptic plasticity, and cognition.


Assuntos
Sinalização do Cálcio , Cálcio/metabolismo , Espinhas Dendríticas/metabolismo , Ácido Glutâmico/metabolismo , Animais , Hipocampo/metabolismo , Memória , Camundongos , Proteína ORAI1 , Células Piramidais/metabolismo , Transdução de Sinais
16.
Nat Commun ; 11(1): 1466, 2020 03 19.
Artigo em Inglês | MEDLINE | ID: mdl-32193428

RESUMO

The positive or negative value (valence) of past experiences is normally integrated into neuronal circuits that encode episodic memories and plays an important role in guiding behavior. Here, we show, using mouse behavioral models, that glutamatergic afferents from the ventral tegmental area to the dorsal hippocampus (VTA→DH) signal negative valence to memory circuits, leading to the formation of fear-inducing context memories and to context-specific reinstatement of fear. To a lesser extent, these projections also contributed to opioid-induced place preference, suggesting a role in signaling positive valence as well, and thus a lack of dedicated polarity. Manipulations of VTA terminal activity were more effective in females and paralleled by sex differences in glutamatergic signaling. By prioritizing retrieval of negative and positive over neutral memories, the VTA→DH circuit can facilitate the selection of adaptive behaviors when current and past experiences are valence congruent.


Assuntos
Hipocampo/fisiologia , Memória/fisiologia , Rede Nervosa/fisiologia , Área Tegmentar Ventral/fisiologia , Animais , Condicionamento Clássico , Giro Denteado/efeitos dos fármacos , Giro Denteado/fisiologia , Medo/fisiologia , Feminino , Inativação Gênica/efeitos dos fármacos , Glutamato Descarboxilase/metabolismo , Glutamatos/metabolismo , Hipocampo/efeitos dos fármacos , Cinética , Masculino , Memória/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Morfina/farmacologia , Rede Nervosa/efeitos dos fármacos , Optogenética , Receptores de N-Metil-D-Aspartato/metabolismo , Caracteres Sexuais , Transmissão Sináptica/efeitos dos fármacos , Transmissão Sináptica/fisiologia , Área Tegmentar Ventral/efeitos dos fármacos , Proteína Vesicular 2 de Transporte de Glutamato/metabolismo
17.
Proc Natl Acad Sci U S A ; 116(43): 21427-21437, 2019 10 22.
Artigo em Inglês | MEDLINE | ID: mdl-31601737

RESUMO

Pharmacology and optogenetics are widely used in neuroscience research to study the central and peripheral nervous systems. While both approaches allow for sophisticated studies of neural circuitry, continued advances are, in part, hampered by technology limitations associated with requirements for physical tethers that connect external equipment to rigid probes inserted into delicate regions of the brain. The results can lead to tissue damage and alterations in behavioral tasks and natural movements, with additional difficulties in use for studies that involve social interactions and/or motions in complex 3-dimensional environments. These disadvantages are particularly pronounced in research that demands combined optogenetic and pharmacological functions in a single experiment. Here, we present a lightweight, wireless, battery-free injectable microsystem that combines soft microfluidic and microscale inorganic light-emitting diode probes for programmable pharmacology and optogenetics, designed to offer the features of drug refillability and adjustable flow rates, together with programmable control over the temporal profiles. The technology has potential for large-scale manufacturing and broad distribution to the neuroscience community, with capabilities in targeting specific neuronal populations in freely moving animals. In addition, the same platform can easily be adapted for a wide range of other types of passive or active electronic functions, including electrical stimulation.


Assuntos
Optogenética/métodos , Farmacologia/métodos , Animais , Encéfalo/metabolismo , Química Encefálica , Channelrhodopsins/metabolismo , Estimulação Elétrica , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Optogenética/instrumentação , Farmacologia/instrumentação , Próteses e Implantes , Tecnologia sem Fio/instrumentação
18.
Nat Neurosci ; 22(4): 618-626, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30858601

RESUMO

Hippocampus, granular retrosplenial cortex (RSCg), and anterior thalamic nuclei (ATN) interact to mediate diverse cognitive functions. To identify cellular mechanisms underlying hippocampo-thalamo-retrosplenial interactions, we investigated the potential circuit suggested by projections to RSCg layer 1 (L1) from GABAergic CA1 neurons and ATN. We find that CA1→RSCg projections stem from GABAergic neurons with a distinct morphology, electrophysiology, and molecular profile. Their long-range axons inhibit L5 pyramidal neurons in RSCg via potent synapses onto apical tuft dendrites in L1. These inhibitory inputs intercept L1-targeting thalamocortical excitatory inputs from ATN to coregulate RSCg activity. Subicular axons, in contrast, excite proximal dendrites in deeper layers. Short-term plasticity differs at each connection. Chemogenetically abrogating CA1→RSCg or ATN→RSCg connections oppositely affects the encoding of contextual fear memory. Our findings establish retrosplenial-projecting CA1 neurons as a distinct class of long-range dendrite-targeting GABAergic neuron and delineate an unusual cortical circuit specialized for integrating long-range inhibition and thalamocortical excitation.


Assuntos
Núcleos Anteriores do Tálamo/citologia , Núcleos Anteriores do Tálamo/fisiologia , Região CA1 Hipocampal/citologia , Região CA1 Hipocampal/fisiologia , Córtex Cerebral/citologia , Córtex Cerebral/fisiologia , Neurônios GABAérgicos/citologia , Neurônios GABAérgicos/fisiologia , Animais , Condicionamento Clássico/fisiologia , Medo/fisiologia , Feminino , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Inibição Neural , Vias Neurais/citologia , Vias Neurais/fisiologia , Neurônios/citologia , Neurônios/fisiologia , Potenciais Sinápticos
19.
Cereb Cortex ; 29(6): 2728-2736, 2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-29878069

RESUMO

Learning to associate stressful events with specific environmental contexts depends on excitatory transmission in the hippocampus, but how this information is transmitted to the neocortex for lasting memory storage is unclear. We identified dorsal hippocampal (DH) projections to the retrosplenial cortex (RSC), which arise mainly from the subiculum and contain either the vesicular glutamate transporter 1 (vGlut1) or vGlut2. Both vGlut1+ and vGlut2+ axons strongly excite and disynaptically inhibit RSC pyramidal neurons in superficial layers, but vGlut2+ axons trigger greater inhibition that spreads to deep layers, indicating that these pathways engage RSC circuits via partially redundant, partially differentiated cellular mechanisms. Using contextual fear conditioning in mice to model contextual associative memories, together with chemogenetic axonal silencing, we found that vGlut1+ projections are principally involved in processing recent context memories whereas vGlut2+ projections contribute to their long-lasting storage. Thus, within the DH→RSC pathway, engagement of vGlut1+ and vGlut2+ circuits differentially contribute to the formation and persistence of fear-inducing context memories.


Assuntos
Córtex Cerebral/fisiologia , Hipocampo/fisiologia , Memória Episódica , Vias Neurais/fisiologia , Animais , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteína Vesicular 1 de Transporte de Glutamato/metabolismo , Proteína Vesicular 2 de Transporte de Glutamato/metabolismo
20.
Psychopharmacology (Berl) ; 236(1): 239-250, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30238131

RESUMO

N-Methyl D-aspartate receptors (NMDAR) are central mediators of glutamate actions underlying learning and memory processes including those required for extinction of fear and fear-related behaviors. Consistent with this view, in animal models, antagonists of NMDAR typically impair fear extinction, whereas partial agonists have facilitating effects. Promoting NMDAR function has thus been recognized as a promising strategy towards reduction of fear symptoms in patients suffering from anxiety disorders and post-traumatic disorder (PTSD). Nevertheless, application of these drugs in clinical trials has proved of limited utility. Here we summarize recent advances in our knowledge of NMDAR pharmacology relevant for fear extinction, focusing on molecular, cellular, and circuit aspects of NMDAR function as they relate to fear extinction at the level of behavior and cognition. We also discuss how these advances from animal models might help to understand and overcome the limitations of existing approaches in human anxiety disorders and how novel, more specific, and personalized approaches might help advance future therapeutic strategies.


Assuntos
Extinção Psicológica/fisiologia , Medo/fisiologia , Receptores de N-Metil-D-Aspartato/metabolismo , Transdução de Sinais/fisiologia , Animais , Transtornos de Ansiedade/tratamento farmacológico , Transtornos de Ansiedade/genética , Transtornos de Ansiedade/metabolismo , Agonistas de Aminoácidos Excitatórios/farmacologia , Agonistas de Aminoácidos Excitatórios/uso terapêutico , Antagonistas de Aminoácidos Excitatórios/farmacologia , Antagonistas de Aminoácidos Excitatórios/uso terapêutico , Extinção Psicológica/efeitos dos fármacos , Medo/efeitos dos fármacos , Humanos , Aprendizagem/efeitos dos fármacos , Aprendizagem/fisiologia , Memória/efeitos dos fármacos , Memória/fisiologia , Subunidades Proteicas/genética , Subunidades Proteicas/metabolismo , Receptores de N-Metil-D-Aspartato/genética , Transdução de Sinais/efeitos dos fármacos , Transtornos de Estresse Pós-Traumáticos/tratamento farmacológico , Transtornos de Estresse Pós-Traumáticos/genética , Transtornos de Estresse Pós-Traumáticos/metabolismo
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