Long-term potentiation prevents ketamine-induced aberrant neurophysiological dynamics in the hippocampus-prefrontal cortex pathway in vivo.

N-methyl-D-aspartate receptor (NMDAr) antagonists such as ketamine (KET) produce psychotic-like behavior in both humans and animal models. NMDAr hypofunction affects normal oscillatory dynamics and synaptic plasticity in key brain regions related to schizophrenia, particularly in the hippocampus and the prefrontal cortex. It has been shown that prior long-term potentiation (LTP) occluded the increase of synaptic efficacy in the hippocampus-prefrontal cortex pathway induced by MK-801, a non-competitive NMDAr antagonist. However, it is not clear whether LTP could also modulate aberrant oscillations and short-term plasticity disruptions induced by NMDAr antagonists. Thus, we tested whether LTP could mitigate the electrophysiological changes promoted by KET. We recorded HPC-PFC local field potentials and evoked responses in urethane anesthetized rats, before and after KET administration, preceded or not by LTP induction. Our results show that KET promotes an aberrant delta-high-gamma cross-frequency coupling in the PFC and an enhancement in HPC-PFC evoked responses. LTP induction prior to KET attenuates changes in synaptic efficiency and prevents the increase in cortical gamma amplitude comodulation. These findings are consistent with evidence that increased efficiency of glutamatergic receptors attenuates cognitive impairment in animal models of psychosis. Therefore, high-frequency stimulation in HPC may be a useful tool to better understand how to prevent NMDAr hypofunction effects on synaptic plasticity and oscillatory coordination in cortico-limbic circuits.

Lithium modulates the muscarinic facilitation of synaptic plasticity and theta-gamma coupling in the hippocampal-prefrontal pathway.

Mood disorders are associated to functional unbalance in mesolimbic and frontal cortical circuits. As a commonly used mood stabilizer, lithium acts through multiple biochemical pathways, including those activated by muscarinic cholinergic receptors crucial for hippocampal-prefrontal communication. Therefore, here we investigated the effects of lithium on prefrontal cortex responses under cholinergic drive. Lithium-treated rats were anesthetized with urethane and implanted with a ventricular cannula for muscarinic activation, a recording electrode in the medial prefrontal cortex (mPFC), and a stimulating electrode in the intermediate hippocampal CA1. Either of two forms of synaptic plasticity, long-term potentiation (LTP) or depression (LTD), were induced during pilocarpine effects, which were monitored in real time through local field potentials. We found that lithium attenuates the muscarinic potentiation of cortical LTP (<20 min) but enhances the muscarinic potentiation of LTD maintenance (>80 min). Moreover, lithium treatment promoted significant cross-frequency coupling between CA1 theta (3-5 Hz) and mPFC low-gamma (30-55 Hz) oscillations. Interestingly, lithium by itself did not affect any of these measures. Thus, lithium pretreatment and muscarinic activation synergistically modulate the hippocampal-prefrontal connectivity. Because these alterations varied with time, oscillatory parameters, and type of synaptic plasticity, our study suggests that lithium influences prefrontal-related circuits through intricate dynamics, informing future experiments on mood disorders.

Interaction between hippocampal-prefrontal plasticity and thalamic-prefrontal activity.

The prefrontal cortex integrates a variety of cognition-related inputs, either unidirectional, e.g., from the hippocampal formation, or bidirectional, e.g., with the limbic thalamus. While the former is usually implicated in synaptic plasticity, the latter is better known for regulating ongoing activity. Interactions between these processes via prefrontal neurons are possibly important for linking mnemonic and executive functions. Our work further elucidates such dynamics using in vivo electrophysiology in rats. First, we report that electrical pulses into CA1/subiculum trigger late-onset (>400 ms) firing responses in the medial prefrontal cortex, which are increased after induction of long-term potentiation. Then, we show these responses to be attenuated by optogenetic control of the paraventricular/mediodorsal thalamic area. This suggests that recruitment and plasticity of the hippocampal-prefrontal pathway is partially related to the thalamic-prefrontal loop. When dysfunctional, this interaction may contribute to cognitive deficits, psychotic symptoms, and seizure generalization, which should motivate future studies combining behavioural paradigms and long-range circuit assessment.

Cannabinoids and Vanilloids in Schizophrenia: Neurophysiological Evidence and Directions for Basic Research.

Much of our knowledge of the endocannabinoid system in schizophrenia comes from behavioral measures in rodents, like prepulse inhibition of the acoustic startle and open-field locomotion, which are commonly used along with neurochemical approaches or drug challenge designs. Such methods continue to map fundamental mechanisms of sensorimotor gating, hyperlocomotion, social interaction, and underlying monoaminergic, glutamatergic, and GABAergic disturbances. These strategies will require, however, a greater use of neurophysiological tools to better inform clinical research. In this sense, electrophysiology and viral vector-based circuit dissection, like optogenetics, can further elucidate how exogenous cannabinoids worsen (e.g., tetrahydrocannabinol, THC) or ameliorate (e.g., cannabidiol, CBD) schizophrenia symptoms, like hallucinations, delusions, and cognitive deficits. Also, recent studies point to a complex endocannabinoid-endovanilloid interplay, including the influence of anandamide (endogenous CB1 and TRPV1 agonist) on cognitive variables, such as aversive memory extinction. In fact, growing interest has been devoted to TRPV1 receptors as promising therapeutic targets. Here, these issues are reviewed with an emphasis on the neurophysiological evidence. First, we contextualize imaging and electrographic findings in humans. Then, we present a comprehensive review on rodent electrophysiology. Finally, we discuss how basic research will benefit from further combining psychopharmacological and neurophysiological tools.

Acetazolamide potentiates the afferent drive to prefrontal cortex in vivo.

The knowledge on real-time neurophysiological effects of acetazolamide is still far behind the wide clinical use of this drug. Acetazolamide - a carbonic anhydrase inhibitor - has been shown to affect the neuromuscular transmission, implying a pH-mediated influence on the central synaptic transmission. To start filling such a gap, we chose a central substrate: hippocampal-prefrontal cortical projections; and a synaptic phenomenon: paired-pulse facilitation (a form of synaptic plasticity) to probe this drug's effects on interareal brain communication in chronically implanted rats. We observed that systemic acetazolamide potentiates the hippocampal-prefrontal paired-pulse facilitation. In addition to this field electrophysiology data, we found that acetazolamide exerts a net inhibitory effect on prefrontal cortical single-unit firing. We propose that systemic acetazolamide reduces the basal neuronal activity of the prefrontal cortex, whereas increasing the afferent drive it receives from the hippocampus. In addition to being relevant to the clinical and side effects of acetazolamide, these results suggest that exogenous pH regulation can have diverse impacts on afferent signaling across the neocortex.

Optogenetic Stimulation of Frontal D1 Neurons Compensates for Impaired Temporal Control of Action in Dopamine-Depleted Mice.

Disrupted mesocortical dopamine contributes to cognitive symptoms of Parkinson's disease (PD). Past work has implicated medial frontal neurons expressing D1 dopamine receptors (D1DRs) in temporal processing. Here, we investigated whether these neurons can compensate for behavioral deficits resulting from midbrain dopamine dysfunction. We report three main results. First, both PD patients and mice with ventral tegmental area (VTA) dopamine depletion had attenuated delta activity (1-4 Hz) in the medial frontal cortex (MFC) during interval timing. Second, we found that optogenetically stimulating MFC D1DR neurons could increase ramping activity among MFC neurons. Finally, stimulating MFC D1DR neurons specifically at delta frequencies (2 Hz) compensated for deficits in temporal control of action caused by VTA dopamine depletion. Our results suggest that cortical networks can be targeted by frequency-specific brain stimulation to improve dopamine-dependent cognitive processing.

Corticostriatal Field Potentials Are Modulated at Delta and Theta Frequencies during Interval-Timing Task in Rodents.

Organizing movements in time is a critical and highly conserved feature of mammalian behavior. Temporal control of action requires corticostriatal networks. We investigate these networks in rodents using a two-interval timing task while recording LFPs in medial frontal cortex (MFC) or dorsomedial striatum. Consistent with prior work, we found cue-triggered delta (1-4 Hz) and theta activity (4-8 Hz) primarily in rodent MFC. We observed delta activity across temporal intervals in MFC and dorsomedial striatum. Rewarded responses were associated with increased delta activity in MFC. Activity in theta bands in MFC and delta bands in the striatum was linked with the timing of responses. These data suggest both delta and theta activity in frontostriatal networks are modulated during interval timing and that activity in these bands may be involved in the temporal control of action.

Infusion of D1 Dopamine Receptor Agonist into Medial Frontal Cortex Disrupts Neural Correlates of Interval Timing.

Medial frontal cortical (MFC) dopamine is essential for the organization of behavior in time. Our prior work indicates that blocking D1 dopamine receptors (D1DR) attenuates temporal processing and low-frequency oscillations by MFC neuronal networks. Here we investigate the effects of focal infusion of the D1DR agonist SKF82958 into MFC during interval timing. MFC D1DR agonist infusion impaired interval timing performance without changing overall firing rates of MFC neurons. MFC ramping patterns of neuronal activity that reflect temporal processing were attenuated following infusion of MFC D1DR agonist. MFC D1DR agonist infusion also altered MFC field potentials by enhancing delta activity between 1 and 4 Hz and attenuating alpha activity between 8 and 15 Hz. These data support the idea that the influence of D1-dopamine signals on frontal neuronal activity adheres to a U-shaped curve, and that cognition requires optimal levels of dopamine in frontal cortex.

Spread of Oropouche virus into the central nervous system in mouse.

Oropouche virus (OROV) is an important cause of arboviral illness in Brazil and other Latin American countries, with most cases clinically manifested as acute febrile illness referred to as Oropouche fever, including myalgia, headache, arthralgia and malaise. However, OROV can also affect the central nervous system (CNS) with clinical neurological implications. Little is known regarding OROV pathogenesis, especially how OROV gains access to the CNS. In the present study, neonatal BALB/c mice were inoculated with OROV by the subcutaneous route and the progression of OROV spread into the CNS was evaluated. Immunohistochemistry revealed that OROV infection advances from posterior parts of the brain, including the periaqueductal gray, toward the forebrain. In the early phases of the infection OROV gains access to neural routes, reaching the spinal cord and ascending to the brain through brainstem regions, with little inflammation. Later, as infection progresses, OROV crosses the blood-brain barrier, resulting in more intense spread into the brain parenchyma, with more severe manifestations of encephalitis.

O ciclo da vesícula sináptica, espinhos dendríticos e a transdução de sinal / Synaptic vesicle cycle, dendritic spines and signal transduction

No sistema nervoso, a sinapse é a estrutura que permite a um neurônio passar um sinal elétrico ou químico a outro neurônio ou outra célula (muscular ou glandular). A palavra sinapse vem de "synaptein", palavra que Sir Charles Scott Sherrington e seus colegas acunharam do grego "syn" (junto) e "haptein"(afivelar). As sinapses podem ser separadas entre elétricas e químicas, porém a maior parte da transmissão sináptica é realizada através das sinapses químicas. Apesar das sinapses químicas terem uma resposta mais lenta que as elétricas, elas possuem a vantagem da amplificação do sinal gerada através de uma cascata de segundos mensageiros. As sinapses químicas podem ser excitatórias ou inibitórias e são caracterizadas por um terminal pré-sináptico (onde estão presentes as vesículas que contêm os neurotransmissores) em contato com um terminal pós-sináptico (onde estão presentes os receptores ionotrópicos e metabotrópicos para esses neurotransmissores) separados pela fenda sináptica. As sinapses típicas acontecem sobre axônios (axo-axônicas), sobre dendritos (axo-dendríticas), sobre o soma de outro neurônio (axo-somáticas) e sobre os espinhos dendríticos...

In the nervous system, the synapse is the structure that allows a neuron pass an electrical or chemical signal to another neuron or another cell (muscle or glandular). The word synapse comes from "synaptein" that Sir Charles Scott Sherrington and his colleagues minted from the Greek "syn" (together) and "haptein"(buckling). Most part of the synaptic transmission is performed through chemical synapses. Chemical synapses have a slower response than the electric ones; they have the advantage of amplifying the signal generated through a cascade of second messengers. Chemical synapses can be excitatory or inhibitory and are characterized by a presynaptic terminal (where there are vesicles that contain the neurotransmitters) in contact with a postsynaptic terminal (where there are the ionotropic and metabotropic receptors) separated by the synaptic cleft. Synapses can occur on axons (axo-axonal), on dendrites (axodendritic), on soma (axo-somatic) and on dendritic spines...

Neurotransmissão glutamatérgica e plasticidade sináptica: aspectos moleculares, clínicos e filogenéticos / Glutamatergic neurotransmission and synaptic plasticity: molecular, clinical, and phylogenetic aspects

A comunicação entre neurônios é passível de constantes modificações, até mesmo no encéfalo adulto. Esta capacidade de circuitos neuronais fortalecerem ou enfraquecerem suas interações sinápticas específicas (fenômeno conhecido como plasticidade sináptica) pode ocorrer de acordo com as diferentes demandas ambientais, o que favorece a noção de que alterações dinâmicas na comunicação entre neurônios estão na base da flexibilidade comportamental (i.e., processos de aprendizagem e memória). Nas últimas décadas, o avanço das neurociências tem permitido uma melhor compreensão a respeito da plasticidade sináptica, especialmente a plasticidade de sinapses glutamatérgicas, cujos processos moleculares de modificação sináptica parecem estar entre os mais comuns de todo o sistema desse progresso na ciência básica tem contribuído para uma melhor compreensão acerca dos processos patológicos envolvendo as sinapses glutamatérgicas, como a doença de Alzheimer. Além disso, a crescente compreensão sobre o funcionamento da comunicação glutamatérgica tem ajudado a esclarecer como as sinapses, em geral, teriam se originado e evoluído na escala filogenética do reino animal (Metazoa)...

Communication between neurons is subject to constant changes, even in the adult brain. This ability of neural circuits to strengthen or weaken their specific synaptic interactions (a phenomenon known assynaptic plasticity) may occur according to different environmental demands, which favors the idea that dynamic changes in the communication between neurons underlie behavioral flexibility (i.e., learning and memory processes). In recent decades, advances in neuroscience has allowed a better understanding of synaptic plasticity, specially the plasticity of glutamatergic synapses, whose molecular processes of synaptic change appear to be among the most common throughout the central nervous system.Much of this progress in basic science has contributed to a better understanding of pathological processes involving the glutamatergic synapses, such as Alzheimer's disease. Furthermore, the growing understanding about the physiology of glutamatergic communication has helped explain how synapses, in general, would have originated and evolved in the phylogenetic scale of the Metazoa...

The unconditioned fear produced by morphine withdrawal is regulated by mu- and kappa-opioid receptors in the midbrain tectum.

We have recently shown that morphine withdrawal sensitizes the neural substrates of fear in the midbrain tectum structures--the dorsal periaqueductal gray (dPAG) and inferior colliculus (IC). In the present study, we investigated the role of mu- and kappa-opioid receptors in the mediation of these effects. Periadolescent rats chronically treated with morphine (10 mg/kg; s.c.) twice daily for 10 days were implanted with an electrode glued to a guide-cannula into the dPAG or the IC. Forty-eight hours after the interruption of this treatment, the effects of intra-dPAG or intra-IC microinjections of [D-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin (DAMGO; 0.6 and 1 nmol/0.2 microl)--a selective mu-receptor agonist--or nor-binaltorphimine (BNI; 2.5 and 5 microg/0.2 microl)--a selective kappa-receptor antagonist with tardive action--on the freezing and escape thresholds determined by electrical stimulation of the dPAG and the IC were examined. For both structures, morphine withdrawal produced pro-aversive effects. DAMGO and BNI had antiaversive effects when injected into the dPAG and IC of non-dependent rats. In morphine-withdrawn rats, only BNI continued to promote antiaversive effects in both structures. Whereas DAMGO lost its antiaversive efficacy when injected into the dPAG, only its highest dose promoted antiaversive effects in the IC of morphine-withdrawn rats, suggesting the development of an apparent tolerance. Thus, the enhanced reactivity of the midbrain tectum in morphine-withdrawn periadolescent rats may be due, at least partially, to an impairment of the inhibitory influence of mechanisms mediated by mu-receptors on the neural substrates of fear in this region.

GABA and opioid mechanisms of the central amygdala underlie the withdrawal-potentiated startle from acute morphine.

Anxiety is an affective symptom common to withdrawal from acute or chronic opiate treatment. Although the potentiation of the acoustic startle reflex has been proposed as an index of increased anxiety, there are variable effects of the opiate withdrawal on the startle reflex in chronic dependence models. On the other hand, withdrawal from acute morphine treatment consistently potentiates the acoustic startle reflex, a response that seems to be mediated by the central nucleus of the amygdala (CeA). However, the underlying neurochemical mechanisms have not been elucidated yet. In the present study, we firstly made a comparison between the effects of the withdrawal from both acute and chronic treatments with morphine on the motor activity and the anxiety-like behavior of rats tested in two experimental models, the acoustic startle reflex and the open-field tests. Our second objective was to investigate the role of GABAergic and opioid mechanisms of the CeA in the modulation of the withdrawal-potentiated startle as a measure of anxiety induced by morphine withdrawal. For the production of chronic dependence, rats received morphine injections (10 mg/kg; s.c.) twice daily during 10 days. Forty-eight hours after the interruption of this treatment, independent groups were probed in the startle reflex and open-field tests. For the acute dependence model, groups of rats were tested in the open field and startle tests under control conditions and under withdrawal from a single injection of morphine (10 mg/kg; s.c.) precipitated by naltrexone injections (0.1 mg/kg; s.c.). The results obtained showed that withdrawal from chronic and acute morphine treatments produced anxiety-like behavior in the open field test, although the anxiogenic-like effects could not be dissociated from the motor effects in the acute dependence model. On the other hand, only the withdrawal from acute morphine treatment significantly potentiated the startle response. Next, we examined the effects of intra-CeA microinjections of muscimol-a GABA(A) receptors agonist-and DAMGO-a mu-opioid receptors agonist-on the potentiated startle induced by acute morphine withdrawal. The results obtained showed that intra-CeA injections of muscimol (1 nmol) and DAMGO (0.5 and 1 nmol) significantly inhibited this response. These findings suggest that the acute dependence model is more suitable to study the aversive effects of morphine withdrawal on the acoustic startle response than the chronic opiate dependence model. Besides, mechanisms mediated by mu- and GABA(A)-receptors in the CeA appear to exert an inhibitory influence on the anxiety-like behavior induced by withdrawal from acute morphine treatment.

Involvement of the midbrain tectum in the unconditioned fear promoted by morphine withdrawal.

The midbrain tectum structures, dorsal periaqueductal gray (dPAG) and inferior colliculus (IC), are involved in the organization of fear and anxiety states during the exposure to dangerous stimuli. Since opiate withdrawal is associated with increased anxiety in both humans and animals, this study aimed to investigate the possible sensitization of the neural substrates of fear in the midbrain tectum and its influence on the morphine withdrawal-induced anxiety. For the production of drug withdrawal, rats received morphine injections (10 mg/kg; s.c.) twice daily during 10 days. Forty-eight hours after the interruption of the chronic treatment, independent groups were probed in the elevated plus-maze and open-field tests. Additional groups of animals were implanted with a bipolar electrode into the dPAG or the IC and submitted to the electrical stimulation of these structures for the determination of the freezing and escape thresholds after 48 h of withdrawal. Our results showed that the morphine withdrawal promoted clear-cut levels of anxiety without the somatic signs of opiate withdrawal. Moreover, morphine-withdrawn rats had an increase in the reactivity to the electrical stimulation of the dPAG and the IC. These findings suggest that the increased anxiety induced by morphine withdrawal is associated with the sensitization of the neural substrates of fear in the dPAG and the IC. So, the present results give support to the hypothesis that withdrawal from chronic treatment with morphine leads to fear states possibly engendered by activation of the dPAG and IC, regardless of the production of somatic symptoms.