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1.
CNS Neurosci Ther ; 30(5): e14739, 2024 05.
Article in English | MEDLINE | ID: mdl-38702935

ABSTRACT

AIMS: The hippocampus has been reported to be morphologically and neurochemically altered in schizophrenia (SZ). Hyperlocomotion is a characteristic SZ-associated behavioral phenotype, which is associated with dysregulated dopamine system function induced by hippocampal hyperactivity. However, the neural mechanism of hippocampus underlying hyperlocomotion remains largely unclear. METHODS: Mouse pups were injected with N-methyl-D-aspartate receptor antagonist (MK-801) or vehicle twice daily on postnatal days (PND) 7-11. In the adulthood phase, one cohort of mice underwent electrode implantation in field CA1 of the hippocampus for the recording local field potentials and spike activity. A separate cohort of mice underwent surgery to allow for calcium imaging of the hippocampus while monitoring the locomotion. Lastly, the effects of atypical antipsychotic (aripiprazole, ARI) were evaluated on hippocampal neural activity. RESULTS: We found that the hippocampal theta oscillations were enhanced in MK-801-treated mice, but the correlation coefficient between the hippocampal spiking activity and theta oscillation was reduced. Consistently, although the rate and amplitude of calcium transients of hippocampal neurons were increased, their synchrony and correlation to locomotion speed were disrupted. ARI ameliorated perturbations produced by the postnatal MK-801 treatment. CONCLUSIONS: These results suggest that the disruption of neural coordination may underly the neuropathological mechanism for hyperlocomotion of SZ.


Subject(s)
Antipsychotic Agents , Aripiprazole , Disease Models, Animal , Dizocilpine Maleate , Hippocampus , Hyperkinesis , Schizophrenia , Animals , Aripiprazole/pharmacology , Aripiprazole/therapeutic use , Schizophrenia/drug therapy , Hippocampus/drug effects , Antipsychotic Agents/pharmacology , Antipsychotic Agents/therapeutic use , Dizocilpine Maleate/pharmacology , Mice , Hyperkinesis/drug therapy , Male , Locomotion/drug effects , Locomotion/physiology , Excitatory Amino Acid Antagonists/pharmacology , Mice, Inbred C57BL , Animals, Newborn , Neurons/drug effects , Theta Rhythm/drug effects , Theta Rhythm/physiology
2.
Sci Rep ; 14(1): 11281, 2024 05 17.
Article in English | MEDLINE | ID: mdl-38760450

ABSTRACT

5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) is a potent classical psychedelic known to induce changes in locomotion, behaviour, and sleep in rodents. However, there is limited knowledge regarding its acute neurophysiological effects. Local field potentials (LFPs) are commonly used as a proxy for neural activity, but previous studies investigating psychedelics have been hindered by confounding effects of behavioural changes and anaesthesia, which alter these signals. To address this gap, we investigated acute LFP changes in the hippocampus (HP) and medial prefrontal cortex (mPFC) of freely behaving rats, following 5-MeO-DMT administration. 5-MeO-DMT led to an increase of delta power and a decrease of theta power in the HP LFPs, which could not be accounted for by changes in locomotion. Furthermore, we observed a dose-dependent reduction in slow (20-50 Hz) and mid (50-100 Hz) gamma power, as well as in theta phase modulation, even after controlling for the effects of speed and theta power. State map analysis of the spectral profile of waking behaviour induced by 5-MeO-DMT revealed similarities to electrophysiological states observed during slow-wave sleep (SWS) and rapid-eye-movement (REM) sleep. Our findings suggest that the psychoactive effects of classical psychedelics are associated with the integration of waking behaviours with sleep-like spectral patterns in LFPs.


Subject(s)
Hippocampus , Prefrontal Cortex , Sleep , Wakefulness , Animals , Prefrontal Cortex/drug effects , Prefrontal Cortex/physiology , Rats , Hippocampus/drug effects , Hippocampus/physiology , Wakefulness/drug effects , Wakefulness/physiology , Male , Sleep/drug effects , Sleep/physiology , Electroencephalography , Theta Rhythm/drug effects , Hallucinogens/pharmacology
3.
Neuroimage ; 293: 120619, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38679186

ABSTRACT

Catecholamines and amino acid transmitter systems are known to interact, the exact links and their impact on cognitive control functions have however remained unclear. Using a multi-modal imaging approach combining EEG and proton-magnetic resonance spectroscopy (1H-MRS), we investigated the effect of different degrees of pharmacological catecholaminergic enhancement onto theta band activity (TBA) as a measure of interference control during response inhibition and execution. It was central to our study to evaluate the predictive impact of in-vivo baseline GABA+ concentrations in the striatum, the anterior cingulate cortex (ACC) and the supplemental motor area (SMA) of healthy adults under varying degrees of methylphenidate (MPH) stimulation. We provide evidence for a predictive interrelation of baseline GABA+ concentrations in cognitive control relevant brain areas onto task-induced TBA during response control stimulated with MPH. Baseline GABA+ concentrations in the ACC, the striatum, and the SMA had a differential impact on predicting interference control-related TBA in response execution trials. GABA+ concentrations in the ACC appeared to be specifically important for TBA modulations when the cognitive effort needed for interference control was high - that is when no prior task experience exists, or in the absence of catecholaminergic enhancement with MPH. The study highlights the predictive role of baseline GABA+ concentrations in key brain areas influencing cognitive control and responsiveness to catecholaminergic enhancement, particularly in high-effort scenarios.


Subject(s)
Catecholamines , Cognition , Electroencephalography , Methylphenidate , Proton Magnetic Resonance Spectroscopy , gamma-Aminobutyric Acid , Humans , gamma-Aminobutyric Acid/metabolism , Male , Adult , Female , Young Adult , Proton Magnetic Resonance Spectroscopy/methods , Catecholamines/metabolism , Methylphenidate/pharmacology , Electroencephalography/methods , Cognition/physiology , Brain/metabolism , Brain/diagnostic imaging , Gyrus Cinguli/metabolism , Gyrus Cinguli/diagnostic imaging , Gyrus Cinguli/drug effects , Theta Rhythm/physiology , Theta Rhythm/drug effects , Executive Function/physiology , Executive Function/drug effects , Central Nervous System Stimulants/pharmacology
4.
J Neurosci ; 44(17)2024 Apr 24.
Article in English | MEDLINE | ID: mdl-38438258

ABSTRACT

Acetylcholine (ACh) is released from basal forebrain cholinergic neurons in response to salient stimuli and engages brain states supporting attention and memory. These high ACh states are associated with theta oscillations, which synchronize neuronal ensembles. Theta oscillations in the basolateral amygdala (BLA) in both humans and rodents have been shown to underlie emotional memory, yet their mechanism remains unclear. Here, using brain slice electrophysiology in male and female mice, we show large ACh stimuli evoke prolonged theta oscillations in BLA local field potentials that depend upon M3 muscarinic receptor activation of cholecystokinin (CCK) interneurons (INs) without the need for external glutamate signaling. Somatostatin (SOM) INs inhibit CCK INs and are themselves inhibited by ACh, providing a functional SOM→CCK IN circuit connection gating BLA theta. Parvalbumin (PV) INs, which can drive BLA oscillations in baseline states, are not involved in the generation of ACh-induced theta, highlighting that ACh induces a cellular switch in the control of BLA oscillatory activity and establishes an internally BLA-driven theta oscillation through CCK INs. Theta activity is more readily evoked in BLA over the cortex or hippocampus, suggesting preferential activation of the BLA during high ACh states. These data reveal a SOM→CCK IN circuit in the BLA that gates internal theta oscillations and suggest a mechanism by which salient stimuli acting through ACh switch the BLA into a network state enabling emotional memory.


Subject(s)
Acetylcholine , Cholecystokinin , Mice, Inbred C57BL , Theta Rhythm , Theta Rhythm/drug effects , Theta Rhythm/physiology , Animals , Male , Mice , Female , Acetylcholine/pharmacology , Acetylcholine/metabolism , Cholecystokinin/pharmacology , Cholecystokinin/metabolism , Interneurons/physiology , Interneurons/drug effects , Somatostatin/metabolism , Somatostatin/pharmacology , Amygdala/physiology , Amygdala/drug effects , Basolateral Nuclear Complex/physiology , Basolateral Nuclear Complex/drug effects , Nerve Net/physiology , Nerve Net/drug effects , Receptor, Muscarinic M3/physiology , Receptor, Muscarinic M3/metabolism , Parvalbumins/metabolism
5.
Int J Mol Sci ; 22(24)2021 Dec 19.
Article in English | MEDLINE | ID: mdl-34948401

ABSTRACT

Theta oscillations generated in hippocampal (HPC) and cortical neuronal networks are involved in various aspects of brain function, including sensorimotor integration, movement planning, memory formation and attention. Disruptions of theta rhythms are present in individuals with brain disorders, including epilepsy and Alzheimer's disease. Theta rhythm generation involves a specific interplay between cellular (ion channel) and network (synaptic) mechanisms. HCN channels are theta modulators, and several medications are known to enhance their activity. We investigated how different doses of lamotrigine (LTG), an HCN channel modulator, and antiepileptic and neuroprotective agent, would affect HPC theta rhythms in acute HPC slices (in vitro) and anaesthetized rats (in vivo). Whole-cell patch clamp recordings revealed that LTG decreased GABAA-fast transmission in CA3 cells, in vitro. In addition, LTG directly depressed CA3 and CA1 pyramidal neuron excitability. These effects were partially blocked by ZD 7288, a selective HCN blocker, and are consistent with decreased excitability associated with antiepileptic actions. Lamotrigine depressed HPC theta oscillations in vitro, also consistent with its neuronal depressant effects. In contrast, it exerted an opposite, enhancing effect, on theta recorded in vivo. The contradictory in vivo and in vitro results indicate that LTG increases ascending theta activating medial septum/entorhinal synaptic inputs that over-power the depressant effects seen in HPC neurons. These results provide new insights into LTG actions and indicate an opportunity to develop more precise therapeutics for the treatment of dementias, memory disorders and epilepsy.


Subject(s)
Action Potentials/drug effects , Anticonvulsants/pharmacology , Hippocampus/drug effects , Lamotrigine/pharmacology , Theta Rhythm/drug effects , Animals , CA3 Region, Hippocampal/cytology , CA3 Region, Hippocampal/drug effects , CA3 Region, Hippocampal/physiology , Hippocampus/cytology , Hippocampus/physiology , Male , Neurons/drug effects , Neurons/metabolism , Rats , Rats, Wistar , Synapses/drug effects , Synapses/physiology , gamma-Aminobutyric Acid/metabolism
6.
PLoS One ; 16(10): e0258939, 2021.
Article in English | MEDLINE | ID: mdl-34695166

ABSTRACT

Urethane, an acute laboratory anesthetic, produces distinct neurophysiological and physiological effects creating an effective model of the dynamics of natural sleep. As a model of both sleep-like neurophysiological activity and the downstream peripheral function urethane is used to model a variety of physiological and pathophysiological processes. As urethane is typically administered as a single-bolus dose, it is unclear the stability of peripheral physiological functions both within and between brain-states under urethane anesthesia. In this present study, we recorded respiration rate and heart rate concurrently with local field potentials from the neocortex and hippocampus to determine the stability of peripheral physiological functions within and between brain-states under urethane anesthesia. Our data shows electroencephalographic characteristics and breathing rate are remarkable stable over long-term recordings within minor reductions in heart rate on the same time scale. Our findings indicate that the use of urethane to model peripheral physiological functions associated with changing brain states are stable during long duration experiments.


Subject(s)
Anesthetics, Intravenous/pharmacology , Brain/drug effects , Theta Rhythm/drug effects , Urethane/pharmacology , Animals , Brain/physiology , Electroencephalography , Male , Rats , Rats, Sprague-Dawley , Respiratory Rate/drug effects , Sleep/drug effects , Sleep/physiology , Theta Rhythm/physiology
7.
Mol Brain ; 14(1): 140, 2021 09 15.
Article in English | MEDLINE | ID: mdl-34526080

ABSTRACT

Previous studies have demonstrated that brain-derived neurotrophic factor (BDNF) is one of the diffusible messengers for enhancing synaptic transmission in the hippocampus. Less information is available about the possible roles of BDNF in the anterior cingulate cortex (ACC). In the present study, we used 64-electrode array field recording system to investigate the effect of BDNF on ACC excitatory transmission. We found that BDNF enhanced synaptic responses in a dose-dependent manner in the ACC in C57/BL6 mice. The enhancement was long-lasting, and persisted for at least 3 h. In addition to the enhancement, BDNF also recruited inactive synaptic responses in the ACC. Bath application of the tropomyosin receptor kinase B (TrkB) receptor antagonist K252a blocked BDNF-induced enhancement. L-type voltage-gated calcium channels (L-VGCC), metabotropic glutamate receptors (mGluRs), but not NMDA receptors were required for BDNF-produced enhancement. Moreover, calcium-stimulated adenylyl cyclase subtype 1 (AC1) but not AC8 was essential for the enhancement. A selective AC1 inhibitor NB001 completely blocked the enhancement. Furthermore, BDNF-produced enhancement occluded theta burst stimulation (TBS) induced long-term potentiation (LTP), suggesting that they may share similar signaling mechanisms. Finally, the expression of BDNF-induced enhancement depends on postsynaptic incorporation of calcium-permeable AMPA receptors (CP-AMPARs) and protein kinase Mζ (PKMζ). Our results demonstrate that cortical BDNF may contribute to synaptic potentiation in the ACC.


Subject(s)
Brain-Derived Neurotrophic Factor/pharmacology , Gyrus Cinguli/drug effects , Long-Term Potentiation/drug effects , Synapses/drug effects , Adenosine Triphosphate/analogs & derivatives , Adenosine Triphosphate/pharmacology , Adenylyl Cyclases/physiology , Animals , Calcium Channels, L-Type/physiology , Carbazoles/pharmacology , Dose-Response Relationship, Drug , Electrodes, Implanted , Indole Alkaloids/pharmacology , Long-Term Potentiation/physiology , Male , Mice , Mice, Inbred C57BL , Protein Kinase C/physiology , Receptors, AMPA/physiology , Receptors, Metabotropic Glutamate/physiology , Synapses/physiology , Theta Rhythm/drug effects
8.
Psychoneuroendocrinology ; 133: 105397, 2021 11.
Article in English | MEDLINE | ID: mdl-34481326

ABSTRACT

Shifts in the peak frequencies of oscillatory neural rhythms have been put forward as a principal mechanism by which cross-frequency coupling and decoupling is implemented in the brain. This notion is based on the mathematical reality that neural oscillations can only fully synchronize when their peak frequencies form harmonic 2:1 relationships (e.g., f2=f1/2). Non-harmonic cross-frequency relationships, on the other hand (based on the irrational golden mean 1.618.:1), provide the highest physiologically possible desynchronized state (reducing the occurrence of spurious, noisy, background coupling), and are therefore anticipated to characterize the resting state of the brain, in which no selective information processing takes place. The present study sought to assess whether the transient occurrence of 1.6:1 non-harmonic and 2:1 harmonic relationships between peak frequencies in the alpha (8-14 Hz) and theta (4-8 Hz) bands - respectively facilitating states of decoupling or coupling between oscillatory rhythms - are impacted by the intranasal administration of a single-dose of oxytocin (OT) or placebo. To do so, continuous resting-state electroencephalography (5 min eyes open, 19 electrodes) was obtained from 96 healthy adult men before and after nasal spray administration. The transient formation of non-harmonic cross-frequency configurations between alpha and theta peak frequencies was significantly increased after OT nasal spray administration, indicating an effect of OT on reducing the intrinsic occurrence of spurious (noisy) background phase synchronizations during resting-state. As a group, the OT group also showed a significant parallel increase in high-frequency and decrease in low-frequency heart rate variability, confirming a homeostatic role of OT in balancing parasympathetic drive. Overall, non-harmonic cross-frequency configurations have been put forward to lay the ground for a healthy neural network allowing the opportunity for an efficient transition from resting state to activity. The observed effects of OT on cross-frequency dynamics are therefore interpreted to reflect a homeostatic role of OT in increasing the signal-to-noise properties of the intrinsic EEG neural frequency architecture, i.e., by precluding the occurrence of 'noisy', unwanted, spurious couplings among neural rhythms in the resting brain.


Subject(s)
Alpha Rhythm , Brain , Oxytocin , Rest , Theta Rhythm , Adult , Alpha Rhythm/drug effects , Brain/drug effects , Brain/physiology , Humans , Male , Nasal Sprays , Oxytocin/administration & dosage , Oxytocin/pharmacology , Theta Rhythm/drug effects
9.
Sci Rep ; 11(1): 16713, 2021 08 18.
Article in English | MEDLINE | ID: mdl-34408180

ABSTRACT

The effects of chronic antidepressant (AD) treatment on sleep disturbances in rodent chronic stress models have not been thoroughly investigated. Here, we show that chronic social defeat stress (SDS) in rats induces prolonged social avoidance, alterations in sleep architecture (increased total rapid eye movement [REM] sleep duration, bout, and shortened REM latency), and contextual but not cued fear memory deficits, even 1 month after the last SDS. These abnormalities were associated with changes in electroencephalography (EEG) spectral powers, including reduced REM sleep theta power during the light phase. Chronic treatment with two different classes of antidepressants (ADs), imipramine and fluoxetine, significantly ameliorated these behavioral, sleep, and EEG abnormalities. Interestingly, REM theta power was normalized by chronic (1 month) but not 1 week AD administration and solely correlated with the ratio (an objective indicator) of social interaction 1 month after the last SDS. These data suggest that reductions in REM sleep theta power, an EEG parameter that has never been directly investigated in humans, is a core sleep symptom in socially defeated rats, and, potentially, also in patients with stress-related psychiatric disorders, including major depressive and posttraumatic stress disorders.


Subject(s)
Antidepressive Agents/adverse effects , Fluoxetine/adverse effects , Imipramine/adverse effects , Sleep, REM/drug effects , Stress, Psychological/physiopathology , Theta Rhythm/drug effects , Animals , Antidepressive Agents/pharmacology , Chronic Disease , Electroencephalography , Fluoxetine/pharmacology , Humans , Imipramine/pharmacology , Male , Rats
10.
Front Neural Circuits ; 15: 699798, 2021.
Article in English | MEDLINE | ID: mdl-34366795

ABSTRACT

The Medial Septum and diagonal Band of Broca (MSDB) was initially studied for its role in locomotion. However, the last several decades were focussed on its intriguing function in theta rhythm generation. Early studies relied on electrical stimulation, lesions and pharmacological manipulation, and reported an inconclusive picture regarding the role of the MSDB circuits. Recent studies using more specific methodologies have started to elucidate the differential role of the MSDB's specific cell populations in controlling both theta rhythm and behaviour. In particular, a novel theory is emerging showing that different MSDB's cell populations project to different brain regions and control distinct aspects of behaviour. While the majority of these behaviours involve movement, increasing evidence suggests that MSDB-related networks govern the motivational aspect of actions, rather than locomotion per se. Here, we review the literature that links MSDB, theta activity, and locomotion and propose open questions, future directions, and methods that could be employed to elucidate the diverse roles of the MSDB-associated networks.


Subject(s)
Locomotion/physiology , Motivation/physiology , Movement/physiology , Nerve Net/physiology , Septal Nuclei/physiology , Theta Rhythm/physiology , Animals , Diagonal Band of Broca/drug effects , Diagonal Band of Broca/physiology , GABA Agonists/pharmacology , Humans , Locomotion/drug effects , Motivation/drug effects , Movement/drug effects , Nerve Net/drug effects , Septal Nuclei/drug effects , Sodium Channel Blockers/pharmacology , Theta Rhythm/drug effects
11.
PLoS Comput Biol ; 17(7): e1009235, 2021 07.
Article in English | MEDLINE | ID: mdl-34329297

ABSTRACT

Theta and gamma rhythms and their cross-frequency coupling play critical roles in perception, attention, learning, and memory. Available data suggest that forebrain acetylcholine (ACh) signaling promotes theta-gamma coupling, although the mechanism has not been identified. Recent evidence suggests that cholinergic signaling is both temporally and spatially constrained, in contrast to the traditional notion of slow, spatially homogeneous, and diffuse neuromodulation. Here, we find that spatially constrained cholinergic stimulation can generate theta-modulated gamma rhythms. Using biophysically-based excitatory-inhibitory (E-I) neural network models, we simulate the effects of ACh on neural excitability by varying the conductance of a muscarinic receptor-regulated K+ current. In E-I networks with local excitatory connectivity and global inhibitory connectivity, we demonstrate that theta-gamma-coupled firing patterns emerge in ACh modulated network regions. Stable gamma-modulated firing arises within regions with high ACh signaling, while theta or mixed theta-gamma activity occurs at the peripheries of these regions. High gamma activity also alternates between different high-ACh regions, at theta frequency. Our results are the first to indicate a causal role for spatially heterogenous ACh signaling in the emergence of localized theta-gamma rhythmicity. Our findings also provide novel insights into mechanisms by which ACh signaling supports the brain region-specific attentional processing of sensory information.


Subject(s)
Cholinergic Neurons/physiology , Gamma Rhythm/physiology , Models, Neurological , Theta Rhythm/physiology , Acetylcholine/pharmacology , Acetylcholine/physiology , Animals , Cholinergic Agents/pharmacology , Cholinergic Neurons/drug effects , Computational Biology , Computer Simulation , Gamma Rhythm/drug effects , Learning/drug effects , Learning/physiology , Nerve Net/drug effects , Nerve Net/physiology , Neural Networks, Computer , Prosencephalon/drug effects , Prosencephalon/physiology , Receptors, Cholinergic/drug effects , Receptors, Cholinergic/physiology , Synaptic Transmission/drug effects , Synaptic Transmission/physiology , Theta Rhythm/drug effects
12.
Clin Neurophysiol ; 132(8): 1770-1776, 2021 08.
Article in English | MEDLINE | ID: mdl-34130243

ABSTRACT

OBJECTIVES: Major Depressive Disorder (MDD) is associated with glutamatergic alterations, including the N-methyl-D-aspartate receptor (NMDA-R). The NMDA-R plays an important role in synaptic plasticity, and individuals with MDD have been shown to have impairments in repetitive Transcranial Magnetic Stimulation (rTMS) motor plasticity. Here, we test whether D-cycloserine, a NMDA-R partial agonist, can rescue TMS motor plasticity in MDD. METHODS: We conducted randomized double-blind placebo-controlled crossover studies in healthy (n = 12) and MDD (n = 12) participants. We stimulated motor cortex using TMS intermittent theta burst stimulation (iTBS) with placebo or D-cycloserine (100 mg). Motor evoked potentials (MEPs) were sampled before and after iTBS. Stimulus response curves (SRC) were characterized at baseline, +90 minutes, and the following day. RESULTS: Acute iTBS MEP facilitation is reduced in MDD and is not rescued by D-cycloserine. After iTBS, SRCs shift to indicate sustained decrease in excitability in healthy participants, yet increased in excitability in MDD participants. D-cycloserine normalized SRC changes from baseline to the following day in MDD participants. In both healthy and MDD participants, D-cycloserine stabilized changes in SRC. CONCLUSION: MDD is associated with alterations in motor plasticity that are rescued and stabilized by NMDA-R agonism. SIGNIFICANCE: Agonism of NMDA receptors rescues iTBS motor plasticity in MDD.


Subject(s)
Cycloserine/therapeutic use , Depressive Disorder, Major/therapy , Motor Cortex/physiology , Neuronal Plasticity/physiology , Theta Rhythm/physiology , Transcranial Magnetic Stimulation/methods , Adult , Cross-Over Studies , Cycloserine/pharmacology , Depressive Disorder, Major/physiopathology , Double-Blind Method , Evoked Potentials, Motor/drug effects , Evoked Potentials, Motor/physiology , Female , Humans , Male , Middle Aged , Motor Cortex/drug effects , Neuronal Plasticity/drug effects , Receptors, N-Methyl-D-Aspartate/agonists , Receptors, N-Methyl-D-Aspartate/physiology , Theta Rhythm/drug effects , Young Adult
13.
Brain Res Bull ; 174: 84-91, 2021 09.
Article in English | MEDLINE | ID: mdl-34090935

ABSTRACT

Hypertension is the most common chronic disease accompanied by cognitive decline and anxiety-like behavior. Angiotensin II (Ang II) induces hypertension by activating angiotensin II receptor subtype 1 (AT1R). The purpose of the study was to examine the potential underlying mechanism of alterations in cognition and anxiety-like behavior induced by Ang II. Adult C57 mice were intraperitoneal injected with either 1 mg/kg/d Ang II or saline individually for 14 consecutive days. Ang II resulted in cognitive decline and anxious like behavior in C57 mice. Moreover, Ang II disturbed bidirectional synaptic plasticity and neural oscillation coupling between high theta and gamma on PP (perforant pathway)-DG (dentate gyrus) pathway. In addition, Ang II decreased the expression of N-methyl-d-aspartate receptor (NR) 2A and NR 2B and increased the expression of GABAAR α1. The data suggest that Ang II disturb neural oscillations via altering excitatory and inhibitory (E/I) balance and eventually damage cognition and anxiety-like behavior in mice.


Subject(s)
Angiotensin II/toxicity , Anxiety/chemically induced , Anxiety/pathology , Behavior, Animal/drug effects , Cognitive Dysfunction/chemically induced , Cognitive Dysfunction/psychology , Gamma Rhythm/drug effects , Theta Rhythm/drug effects , Animals , Dentate Gyrus/drug effects , Male , Maze Learning/drug effects , Mice , Mice, Inbred C57BL , Neural Pathways/drug effects , Neuronal Plasticity/drug effects , Receptors, GABA-A/biosynthesis , Receptors, GABA-A/drug effects , Receptors, N-Methyl-D-Aspartate/biosynthesis , Recognition, Psychology/drug effects
14.
Exp Neurol ; 343: 113743, 2021 09.
Article in English | MEDLINE | ID: mdl-34000250

ABSTRACT

Despite the development of multiple pharmacological approaches over the years aimed at treating Alzheimer's Disease (AD) only very few have been approved for clinical use in patients. To date there still exists no disease-modifying treatment that could prevent or rescue the cognitive impairment, particularly of memory aquisition, that is characteristic of AD. One of the possibilities for this state of affairs might be that the majority of drug discovery efforts focuses on outcome measures of decreased neuropathological biomarkers characteristic of AD, without taking into acount neuronal processes essential to the generation and maintenance of memory processes. Particularly, the capacity of the brain to generate theta (θ) and gamma (γ) oscillatory activity has been strongly correlated to memory performance. Using a systematic review approach, we synthesize the existing evidence in the literature on pharmacological interventions that enhance neuronal theta (θ) and/or gamma (γ) oscillations in non-pathological animal models and in AD animal models. Additionally, we synthesize the main outcomes and neurochemical systems targeted. We propose that functional biomarkers such as cognition-relevant neuronal network oscillations should be used as outcome measures during the process of research and development of novel drugs against cognitive impairment in AD.


Subject(s)
Alzheimer Disease/drug therapy , Brain/drug effects , Gamma Rhythm/drug effects , Nerve Net/drug effects , Nootropic Agents/administration & dosage , Theta Rhythm/drug effects , Alzheimer Disease/physiopathology , Animals , Brain/physiology , Cholinergic Agents/administration & dosage , Dopamine Agents/administration & dosage , Drug Evaluation, Preclinical/methods , Electroencephalography/drug effects , Electroencephalography/methods , Gamma Rhythm/physiology , Humans , Memory Disorders/drug therapy , Memory Disorders/physiopathology , Nerve Net/physiology , Theta Rhythm/physiology , Treatment Outcome
15.
Neuromolecular Med ; 23(3): 416-427, 2021 09.
Article in English | MEDLINE | ID: mdl-33398803

ABSTRACT

Theta and gamma rhythms in hippocampus are important to cognitive performance. The cognitive impairments following cerebral ischemia is linked with the dysfunction of theta and gamma oscillations. As the primary mechanism for learning and memory, synaptic plasticity is in connection with these neural oscillations. Although vascular endothelial growth factor (VEGF) is thought to protect synaptic function in the ischemia rats to relieve cognitive impairment, little has been done on its effect of neural dynamics with this process. The present study investigated whether the alternation of neural oscillations in the hippocampus of ischemia rats is one of the potential neuroprotective mechanisms of VEGF. Rats were treated with the intranasal administration of VEGF at 72 h following chronic global cerebral ischemia procedure. Then local field potentials (LFPs) in hippocampal CA1 and CA3 regions were recorded and analyzed. Our results showed that VEGF can improve the power of theta and gamma rhythms in CA1 region after ischemia. Chronic global cerebral ischemia reduced the theta-gamma phase-amplitude coupling (PAC) not only within CA1 area but also in the pathway from CA3 to CA1, while VEGF alleviated the decreased coupling strength. Despite these notable differences, there were no obvious changes in the PAC within CA3 region. Surprisingly, the ischemia state did not affect the phase-phase interaction of hippocampus. In conclusion, our findings demonstrated that VEGF enhanced the theta-gamma PAC strength of CA3-CA1 pathway in ischemia rats, which may futher improve the information transmission within the hippocampus. These results illustrated the potential electrophysiologic mechanism of VEGF on cognitive improvement.


Subject(s)
Brain Ischemia/physiopathology , CA1 Region, Hippocampal/metabolism , CA3 Region, Hippocampal/metabolism , Vascular Endothelial Growth Factor A/therapeutic use , Administration, Intranasal , Animals , Brain Ischemia/metabolism , Carotid Stenosis , Chronic Disease , Cognition Disorders/etiology , Cognition Disorders/therapy , Gamma Rhythm/drug effects , Male , Membrane Potentials/drug effects , Models, Animal , Random Allocation , Rats , Rats, Wistar , Recombinant Proteins/administration & dosage , Recombinant Proteins/pharmacology , Recombinant Proteins/therapeutic use , Single-Blind Method , Theta Rhythm/drug effects , Vascular Endothelial Growth Factor A/administration & dosage , Vascular Endothelial Growth Factor A/pharmacology , Vascular Endothelial Growth Factor A/physiology
16.
Cereb Cortex ; 31(1): 575-590, 2021 01 01.
Article in English | MEDLINE | ID: mdl-32901273

ABSTRACT

Intermittent theta-burst stimulation (iTBS), a form of repetitive transcranial magnetic stimulation, is considered a potential therapy for treatment-resistant depression. The synaptic mechanism of iTBS has long been known to be an effective method to induce long-term potentiation (LTP)-like plasticity in humans. However, there is limited evidence as to whether the antidepressant effect of iTBS is associated with change in synaptic function in the prefrontal cortex (PFC) in preclinical study. Hence, we applied an antidepressant (i.e., fluoxetine)-resistant depression rat model induced by severe foot-shocks to investigate the antidepressant efficacy of iTBS in the synaptic pathology. The results showed that iTBS treatment improved not only the impaired LTP, but also the aberrant long-term depression in the PFC of antidepressant-resistant depression model rats. Moreover, the mechanism of LTP improvement by iTBS involved downstream molecules of brain-derived neurotrophic factor, while the mechanism of long-term depression improvement by iTBS involved downstream molecules of proBDNF. The aberrant spine morphology was also improved by iTBS treatment. This study demonstrated that the mechanism of the iTBS paradigm is complex and may regulate not only excitatory but also inhibitory synaptic effects in the PFC.


Subject(s)
Antidepressive Agents/pharmacology , Depressive Disorder, Treatment-Resistant/physiopathology , Neuronal Plasticity/physiology , Prefrontal Cortex/physiopathology , Synapses/pathology , Animals , Evoked Potentials, Motor/drug effects , Evoked Potentials, Motor/physiology , Long-Term Potentiation/physiology , Male , Motor Cortex/drug effects , Motor Cortex/physiopathology , Neuronal Plasticity/drug effects , Prefrontal Cortex/drug effects , Rats, Sprague-Dawley , Theta Rhythm/drug effects , Theta Rhythm/physiology , Transcranial Magnetic Stimulation/methods
17.
Clin Neurophysiol ; 132(1): 25-35, 2021 01.
Article in English | MEDLINE | ID: mdl-33248432

ABSTRACT

OBJECTIVE: To determine the quantitative EEG responses in a population of drug-naïve patients with Temporal Lobe Epilepsy (TLE) after Levetiracetam (LEV) initiation as first antiepileptic drug (AED). We hypothesized that the outcome of AED treatment can be predicted from EEG data in patients with TLE. METHODS: Twenty-three patients with TLE and twenty-five healthy controls were examined. Clinical outcome was dichotomized into seizure-free (SF) and non-seizure-free (NSF) after two years of LEV. EEG parameters were compared between healthy controls and patients with TLE at baseline (EEGpre) and after three months of AED therapy (EEGpre-post) and between SF and NSF patients. Receiver Operating Characteristic curves models were built to test whether EEG parameters predicted outcome. RESULTS: AED therapy induces an increase in EEG power for Alpha (p = 0.06) and a decrease in Theta (p < 0.05). Connectivity values were lower in SF compared to NSF patients (p < 0.001). Quantitative EEG predicted outcome after LEV treatment with an estimated accuracy varying from 65.2% to 91.3% (area under the curve [AUC] = 0.56-0.93) for EEGpre and from 69.9% to 86.9% (AUC = 0.69-0.94) for EEGpre-post. CONCLUSIONS: AED therapy induces EEG modifications in TLE patients, and such modifications are predictive of clinical outcome. SIGNIFICANCE: Quantitative EEG may help understanding the effect of AEDs in the central nervous system and offer new prognostic biomarkers for patients with epilepsy.


Subject(s)
Anticonvulsants/pharmacology , Electroencephalography/drug effects , Epilepsy, Temporal Lobe/drug therapy , Levetiracetam/pharmacology , Adult , Aged , Alpha Rhythm/drug effects , Alpha Rhythm/physiology , Analysis of Variance , Area Under Curve , Beta Rhythm/drug effects , Brain/physiology , Case-Control Studies , Connectome , Delta Rhythm/drug effects , Electroencephalography/methods , Electroencephalography Phase Synchronization/drug effects , Electroencephalography Phase Synchronization/physiology , Epilepsy, Temporal Lobe/physiopathology , Female , Gamma Rhythm/drug effects , Humans , Male , Middle Aged , Prognosis , ROC Curve , Reproducibility of Results , Retrospective Studies , Theta Rhythm/drug effects , Theta Rhythm/physiology , Young Adult
18.
Sci Rep ; 10(1): 18981, 2020 11 04.
Article in English | MEDLINE | ID: mdl-33149202

ABSTRACT

Changes in oscillatory activity are widely reported after subanesthetic ketamine, however their mechanisms of generation are unclear. Here, we tested the hypothesis that nasal respiration underlies the emergence of high-frequency oscillations (130-180 Hz, HFO) and behavioral activation after ketamine in freely moving rats. We found ketamine 20 mg/kg provoked "fast" theta sniffing in rodents which correlated with increased locomotor activity and HFO power in the OB. Bursts of ketamine-dependent HFO were coupled to "fast" theta frequency sniffing. Theta coupling of HFO bursts were also found in the prefrontal cortex and ventral striatum which, although of smaller amplitude, were coherent with OB activity. Haloperidol 1 mg/kg pretreatment prevented ketamine-dependent increases in fast sniffing and instead HFO coupling to slower basal respiration. Consistent with ketamine-dependent HFO being driven by nasal respiration, unilateral naris blockade led to an ipsilateral reduction in ketamine-dependent HFO power compared to the control side. Bilateral nares blockade reduced ketamine-induced hyperactivity and HFO power and frequency. These findings suggest that nasal airflow entrains ketamine-dependent HFO in diverse brain regions, and that the OB plays an important role in the broadcast of this rhythm.


Subject(s)
Excitatory Amino Acid Antagonists/administration & dosage , Ketamine/administration & dosage , Motor Activity/drug effects , Nose/physiology , Respiration/drug effects , Animals , Behavior, Animal/drug effects , Excitatory Amino Acid Antagonists/pharmacology , Haloperidol/adverse effects , Ketamine/pharmacology , Male , Nose/drug effects , Prefrontal Cortex/drug effects , Prefrontal Cortex/physiology , Rats , Rats, Wistar , Theta Rhythm/drug effects , Ventral Striatum/drug effects , Ventral Striatum/physiology
19.
Cell Rep ; 33(8): 108415, 2020 11 24.
Article in English | MEDLINE | ID: mdl-33238116

ABSTRACT

Salient visual stimuli enhance theta oscillations and spike-phase locking in the theta band in the primary visual cortex (V1) of mice; however, the detailed mechanisms remain unknown. GABAergic neurons play a vital role in regulating these oscillations. Here, we use optogenetic recordings to tag cell-type-specific neurons in V1 of head-fixed mice and demonstrate that salient visual stimuli facilitate somatostatin (SOM)-expressing neuron responses and firing with theta band oscillations but suppress activities of parvalbumin (PV)-expressing neurons. Furthermore, inactivation of SOM neurons attenuates the enhancement of theta oscillations induced by salient visual stimuli and rhythmic activation of SOM neurons enhances theta oscillations. These results reveal a potential cortical theta oscillation mechanism governed by SOM neurons.


Subject(s)
Neurons/drug effects , Somatostatin/therapeutic use , Theta Rhythm/drug effects , Animals , Humans , Mice , Photic Stimulation , Signal Transduction , Somatostatin/pharmacology
20.
Curr Biol ; 30(18): 3556-3569.e5, 2020 09 21.
Article in English | MEDLINE | ID: mdl-32707066

ABSTRACT

Prenatal alcohol exposure (PAE) leads to profound deficits in spatial memory and synaptic and cellular alterations to the hippocampus that last into adulthood. Neurons in the hippocampus called place cells discharge as an animal enters specific places in an environment, establish distinct ensemble codes for familiar and novel places, and are modulated by local theta rhythms. Spatial memory is thought to critically depend on the integrity of hippocampal place cell firing. Therefore, we tested the hypothesis that hippocampal place cell firing is impaired after PAE by performing in vivo recordings from the hippocampi (CA1 and CA3) of moderate PAE and control adult rats. Our results show that hippocampal CA3 neurons from PAE rats have reduced spatial tuning. Second, CA1 and CA3 neurons from PAE rats are less likely to orthogonalize their firing between directions of travel on a linear track and between changes in contextual stimuli in an open arena compared to control neurons. Lastly, reductions in the number of hippocampal place cells exhibiting significant theta rhythmicity and phase precession were observed, which may suggest changes to hippocampal microcircuit function. Together, the reduced spatial tuning and sensitivity to contextual changes provide a neural systems-level mechanism to explain spatial memory impairment after moderate PAE.


Subject(s)
Action Potentials , Alcohol Drinking/adverse effects , CA1 Region, Hippocampal/pathology , CA3 Region, Hippocampal/pathology , Maternal Exposure/adverse effects , Prenatal Exposure Delayed Effects/pathology , Theta Rhythm/drug effects , Animals , CA1 Region, Hippocampal/drug effects , CA3 Region, Hippocampal/drug effects , Female , Male , Neurons/drug effects , Neurons/pathology , Pregnancy , Prenatal Exposure Delayed Effects/etiology , Rats , Rats, Long-Evans , Spatial Memory
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