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1.
Nat Commun ; 14(1): 3972, 2023 07 05.
Article in English | MEDLINE | ID: mdl-37407557

ABSTRACT

Dysregulated fear reactions can result from maladaptive processing of trauma-related memories. In post-traumatic stress disorder (PTSD) and other psychiatric disorders, dysfunctional extinction learning prevents discretization of trauma-related memory engrams and generalizes fear responses. Although PTSD may be viewed as a memory-based disorder, no approved treatments target pathological fear memory processing. Hippocampal sharp wave-ripples (SWRs) and concurrent neocortical oscillations are scaffolds to consolidate contextual memory, but their role during fear processing remains poorly understood. Here, we show that closed-loop, SWR triggered neuromodulation of the medial forebrain bundle (MFB) can enhance fear extinction consolidation in male rats. The modified fear memories became resistant to induced recall (i.e., 'renewal' and 'reinstatement') and did not reemerge spontaneously. These effects were mediated by D2 receptor signaling-induced synaptic remodeling in the basolateral amygdala. Our results demonstrate that SWR-triggered closed-loop stimulation of the MFB reward system enhances extinction of fearful memories and reducing fear expression across different contexts and preventing excessive and persistent fear responses. These findings highlight the potential of neuromodulation to augment extinction learning and provide a new avenue to develop treatments for anxiety disorders.


Subject(s)
Basolateral Nuclear Complex , Stress Disorders, Post-Traumatic , Rats , Male , Animals , Fear/physiology , Extinction, Psychological/physiology , Memory/physiology , Mental Recall/physiology , Basolateral Nuclear Complex/physiology , Memory Disorders
2.
Neuron ; 111(13): 2065-2075.e5, 2023 07 05.
Article in English | MEDLINE | ID: mdl-37164008

ABSTRACT

Although the etiology of major depressive disorder remains poorly understood, reduced gamma oscillations is an emerging biomarker. Olfactory bulbectomy, an established model of depression that reduces limbic gamma oscillations, suffers from non-specific effects of structural damage. Here, we show that transient functional suppression of olfactory bulb neurons or their piriform cortex efferents decreased gamma oscillation power in limbic areas and induced depression-like behaviors in rodents. Enhancing transmission of gamma oscillations from olfactory bulb to limbic structures by closed-loop electrical neuromodulation alleviated these behaviors. By contrast, silencing gamma transmission by anti-phase closed-loop stimulation strengthened depression-like behaviors in naive animals. These induced behaviors were neutralized by ketamine treatment that restored limbic gamma power. Taken together, our results reveal a causal link between limbic gamma oscillations and depression-like behaviors in rodents. Interfering with these endogenous rhythms can affect behaviors in rodent models of depression, suggesting that restoring gamma oscillations may alleviate depressive symptoms.


Subject(s)
Depressive Disorder, Major , Olfactory Bulb , Animals , Olfactory Bulb/physiology , Rodentia , Depression/therapy , Neurons
3.
Front Neural Circuits ; 15: 701080, 2021.
Article in English | MEDLINE | ID: mdl-34305537

ABSTRACT

The medial septum (MS), as part of the basal forebrain, supports many physiological functions, from sensorimotor integration to cognition. With often reciprocal connections with a broad set of peers at all major divisions of the brain, the MS orchestrates oscillatory neuronal activities throughout the brain. These oscillations are critical in generating sensory and emotional salience, locomotion, maintaining mood, supporting innate anxiety, and governing learning and memory. Accumulating evidence points out that the physiological oscillations under septal influence are frequently disrupted or altered in pathological conditions. Therefore, the MS may be a potential target for treating neurological and psychiatric disorders with abnormal oscillations (oscillopathies) to restore healthy patterns or erase undesired ones. Recent studies have revealed that the patterned stimulation of the MS alleviates symptoms of epilepsy. We discuss here that stimulus timing is a critical determinant of treatment efficacy on multiple time scales. On-demand stimulation may dramatically reduce side effects by not interfering with normal physiological functions. A precise pattern-matched stimulation through adaptive timing governed by the ongoing oscillations is essential to effectively terminate pathological oscillations. The time-targeted strategy for the MS stimulation may provide an effective way of treating multiple disorders including Alzheimer's disease, anxiety/fear, schizophrenia, and depression, as well as pain.


Subject(s)
Brain Diseases/physiopathology , Brain Waves/physiology , Brain/physiopathology , Deep Brain Stimulation/methods , Septal Nuclei/physiopathology , Animals , Brain Diseases/therapy , Epilepsy/physiopathology , Epilepsy/therapy , Humans , Mental Disorders/physiopathology , Mental Disorders/therapy , Treatment Outcome
4.
PLoS Biol ; 16(6): e2004712, 2018 06.
Article in English | MEDLINE | ID: mdl-29939998

ABSTRACT

Evolutionary development of vision has provided us with the capacity to detect moving objects. Concordant shifts of visual features suggest movements of the observer, whereas discordant changes are more likely to be indicating independently moving objects, such as predators or prey. Such distinction helps us to focus attention, adapt our behavior, and adjust our motor patterns to meet behavioral challenges. However, the neural basis of distinguishing self-induced and self-independent visual motions is not clarified in unrestrained animals yet. In this study, we investigated the presence and origin of motion-related visual information in the striatum of rats, a hub of action selection and procedural memory. We found that while almost half of the neurons in the dorsomedial striatum are sensitive to visual motion congruent with locomotion (and that many of them also code for spatial location), only a small subset of them are composed of fast-firing interneurons that could also perceive self-independent visual stimuli. These latter cells receive their visual input at least partially from the secondary visual cortex (V2). This differential visual sensitivity may be an important support in adjusting behavior to salient environmental events. It emphasizes the importance of investigating visual motion perception in unrestrained animals.


Subject(s)
Corpus Striatum/physiology , Motion Perception/physiology , Neurons/metabolism , Visual Cortex/physiology , Animals , Cues , Male , Photic Stimulation , Rats , Rats, Long-Evans , Vision, Ocular/physiology
5.
J Neurophysiol ; 111(5): 1132-49, 2014 Mar.
Article in English | MEDLINE | ID: mdl-24353300

ABSTRACT

Monitoring representative fractions of neurons from multiple brain circuits in behaving animals is necessary for understanding neuronal computation. Here, we describe a system that allows high-channel-count recordings from a small volume of neuronal tissue using a lightweight signal multiplexing headstage that permits free behavior of small rodents. The system integrates multishank, high-density recording silicon probes, ultraflexible interconnects, and a miniaturized microdrive. These improvements allowed for simultaneous recordings of local field potentials and unit activity from hundreds of sites without confining free movements of the animal. The advantages of large-scale recordings are illustrated by determining the electroanatomic boundaries of layers and regions in the hippocampus and neocortex and constructing a circuit diagram of functional connections among neurons in real anatomic space. These methods will allow the investigation of circuit operations and behavior-dependent interregional interactions for testing hypotheses of neural networks and brain function.


Subject(s)
Behavior, Animal/physiology , Cerebral Cortex/physiology , Electrodes, Implanted , Nerve Net/physiology , Neurons/physiology , Signal Processing, Computer-Assisted , Animals , Cerebral Cortex/surgery , Male , Mice , Nerve Net/surgery , Rats , Rats, Long-Evans , Software
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