-
Nature Neuroscience Jan 2018Musicians can perform at different tempos, speakers can control the cadence of their speech, and children can flexibly vary their temporal expectations of events. To...
Musicians can perform at different tempos, speakers can control the cadence of their speech, and children can flexibly vary their temporal expectations of events. To understand the neural basis of such flexibility, we recorded from the medial frontal cortex of nonhuman primates trained to produce different time intervals with different effectors. Neural responses were heterogeneous, nonlinear, and complex, and they exhibited a remarkable form of temporal invariance: firing rate profiles were temporally scaled to match the produced intervals. Recording from downstream neurons in the caudate and from thalamic neurons projecting to the medial frontal cortex indicated that this phenomenon originates within cortical networks. Recurrent neural network models trained to perform the task revealed that temporal scaling emerges from nonlinearities in the network and that the degree of scaling is controlled by the strength of external input. These findings demonstrate a simple and general mechanism for conferring temporal flexibility upon sensorimotor and cognitive functions.
Topics: Action Potentials; Animals; Brain; Electric Stimulation; Female; GABA-A Receptor Agonists; Macaca mulatta; Magnetic Resonance Imaging; Male; Models, Neurological; Models, Theoretical; Motor Activity; Muscimol; Neural Pathways; Neurons; Statistics, Nonparametric; Time Perception
PubMed: 29203897
DOI: 10.1038/s41593-017-0028-6 -
PLoS Biology Dec 2019Social transmission of freezing behavior has been conceived of as a one-way phenomenon in which an observer "catches" the fear of another. Here, we use a paradigm in...
Social transmission of freezing behavior has been conceived of as a one-way phenomenon in which an observer "catches" the fear of another. Here, we use a paradigm in which an observer rat witnesses another rat receiving electroshocks. Bayesian model comparison and Granger causality show that rats exchange information about danger in both directions: how the observer reacts to the demonstrator's distress also influences how the demonstrator responds to the danger. This was true to a similar extent across highly familiar and entirely unfamiliar rats but is stronger in animals preexposed to shocks. Injecting muscimol in the anterior cingulate of observers reduced freezing in the observers and in the demonstrators receiving the shocks. Using simulations, we support the notion that the coupling of freezing across rats could be selected for to more efficiently detect dangers in a group, in a way similar to cross-species eavesdropping.
Topics: Animal Communication; Animals; Bayes Theorem; Behavior, Animal; Fear; Freezing Reaction, Cataleptic; Gyrus Cinguli; Male; Muscimol; Rats; Rats, Long-Evans; Rats, Sprague-Dawley; Social Behavior
PubMed: 31805039
DOI: 10.1371/journal.pbio.3000524 -
Neurobiology of Learning and Memory Oct 2021The amygdala is a collection of nuclei that support adaptive social behavior and are implicated in disorders such as autism. The basolateral complex of the amygdala...
The amygdala is a collection of nuclei that support adaptive social behavior and are implicated in disorders such as autism. The basolateral complex of the amygdala (BLA), a main subdivision of the amygdala, influences fear responses, motivated behavior, and memory of emotional events via its communication with other amygdalar nuclei and with other brain regions such as the prefrontal cortex, striatum, and hippocampus. The specific role of the BLA in responses to social stimuli is less clear. The present study of female rats investigated the role of the BLA in responding to socially-relevant information by asking how inactivation of the BLA with bilateral infusions of the GABA receptor agonist muscimol would affect spontaneous exploration of wood blocks scented either with conspecific male or female urine or with nonsocial odorants. Conspecific urine samples were used because urine conveys information about sex, health, social status, and reproductive state in rodents. The results revealed that BLA inactivation reduced female rats' spontaneous preference for social odors over nonsocial odors, specifically for female urine. However, BLA inactivation did not generally impair rats' ability to distinguish two odors from the same category (e.g., urine odors from two different male rats). The results indicate that the BLA is important for responding to salience of social stimuli but not for discriminating between different individuals, a result that has important implications for amygdalar modulation of downstream attention, motivation, and memory processes for social stimuli.
Topics: Animals; Basolateral Nuclear Complex; Estrous Cycle; Female; Habituation, Psychophysiologic; Muscimol; Odorants; Rats; Rats, Long-Evans; Social Behavior
PubMed: 34271138
DOI: 10.1016/j.nlm.2021.107489 -
Scientific Reports Mar 2019The infralimbic (IL) and prelimbic (PL) cortices of the medial prefrontal cortex (mPFC) have been shown to differentially control context-dependent behavior, with the PL...
The infralimbic (IL) and prelimbic (PL) cortices of the medial prefrontal cortex (mPFC) have been shown to differentially control context-dependent behavior, with the PL implicated in the expression of contextually conditioned fear and drug-seeking, and the IL in the suppression of these behaviors. However, the roles of these subregions in contextually driven natural reward-seeking remain relatively underexplored. The present study further examined the functional dichotomy within the mPFC in the contextual control over cued reward-seeking, using a contextual biconditional discrimination (CBD) task. Rats were first trained to emit a nose poke response to the presentation of an auditory stimulus (e.g., X) for the delivery of sucrose reward, and to withhold a nose poke response to the presentation of another auditory stimulus (e.g., Y) in a context-specific manner (e.g. Context A: X+, Y-; Context B: X-, Y+). Following acquisition, rats received bilateral microinjections of GABA receptor agonists (muscimol and baclofen), or saline into the IL or PL, prior to a CBD training session and a probe test (under extinction conditions). Both IL and PL inactivation resulted in robust impairment in CBD performance, indicating that both subregions are involved in the processing of appetitively motivated contextual memories in reward-seeking.
Topics: Animals; Baclofen; Behavior, Animal; Conditioning, Operant; Drug-Seeking Behavior; Extinction, Psychological; GABA Agonists; Male; Muscimol; Prefrontal Cortex; Rats; Rats, Long-Evans; Reward
PubMed: 30850668
DOI: 10.1038/s41598-019-40532-7 -
Journal of Neurophysiology Feb 2020The interplay between inhibition and excitation can regulate behavioral expression and control, including the expression of communicative behaviors like birdsong....
The interplay between inhibition and excitation can regulate behavioral expression and control, including the expression of communicative behaviors like birdsong. Computational models postulate varying degrees to which inhibition within vocal motor circuitry influences birdsong, but few studies have tested these models by manipulating inhibition. Here we enhanced and attenuated inhibition in the cortical nucleus HVC (used as proper name) of Bengalese finches ( var. ). Enhancement of inhibition (with muscimol) in HVC dose-dependently reduced the amount of song produced. Infusions of higher concentrations of muscimol caused some birds to produce spectrally degraded songs, whereas infusions of lower doses of muscimol led to the production of relatively normal (nondegraded) songs. However, the spectral and temporal structures of these nondegraded songs were significantly different from songs produced under control conditions. In particular, muscimol infusions decreased the frequency and amplitude of syllables, increased various measures of acoustic entropy, and increased the variability of syllable structure. Muscimol also increased sequence durations and the variability of syllable timing and syllable sequencing. Attenuation of inhibition (with bicuculline) in HVC led to changes to song distinct from and often opposite to enhancing inhibition. For example, in contrast to muscimol, bicuculline infusions increased syllable amplitude, frequency, and duration and decreased the variability of acoustic features. However, like muscimol, bicuculline increased the variability of syllable sequencing. These data highlight the importance of inhibition to the production of stereotyped vocalizations and demonstrate that changes to neural dynamics within cortical circuitry can differentially affect spectral and temporal features of song. We reveal that manipulations of inhibition in the cortical nucleus HVC affect the structure, timing, and sequencing of syllables in Bengalese finch song. Enhancing and blocking inhibition led to opposite changes to the acoustic structure and timing of vocalizations, but both caused similar changes to vocal sequencing. These data provide support for computational models of song control but also motivate refinement of existing models to account for differential effects on syllable structure, timing, and sequencing.
Topics: Animals; Bicuculline; Cerebral Cortex; Finches; GABA-A Receptor Agonists; GABA-A Receptor Antagonists; Male; Muscimol; Neural Inhibition; Vocalization, Animal
PubMed: 31967928
DOI: 10.1152/jn.00142.2019 -
Neurobiology of Learning and Memory Nov 2017Episodic memory was initially believed to be unique to humans. However, studies demonstrate that nonhuman species discriminate items based on the triad what, where and...
Episodic memory was initially believed to be unique to humans. However, studies demonstrate that nonhuman species discriminate items based on the triad what, where and when. Here we addressed the role of the dorsal hippocampal subfield CA1 in an integrative what-where-when task in Wistar rats. We performed bilateral inactivation of dorsal CA1 with the GABA agonist muscimol previously to the task. As expected, sham-operated animals recollected an integrative memory for objects (what), their places (where) and temporal order (when). However, the inactivation of CA1 impaired the performance of the three components of episodic-like memory. In addition, total time of objects exploration and distance traveled were not different between groups, indicating that rats had similar levels of motivation, thus, alterations in exploration does not account for impaired locomotor performance. Altogether, our data provides evidence that CA1 plays an important role in episodic-like memory.
Topics: Animals; CA1 Region, Hippocampal; Exploratory Behavior; GABA-A Receptor Agonists; Male; Memory, Episodic; Muscimol; Rats, Wistar
PubMed: 28843666
DOI: 10.1016/j.nlm.2017.08.008 -
Brain Research Apr 2022The central nucleus of the amygdala (CNA) projects to brainstem regions that generate and regulate rapid eye movement sleep (REM). We used optogenetics to assess the...
The central nucleus of the amygdala (CNA) projects to brainstem regions that generate and regulate rapid eye movement sleep (REM). We used optogenetics to assess the influence of CNA inputs into reticularis pontis oralis (RPO), pedunculopontine tegmentum (PPT) and nucleus subcoeruleus (SubC) on dark period sleep. We compared these results to effects of microinjections into CNA of the GABA agonist, muscimol (MUS, inhibition of cell bodies) and tetrodotoxin (TTX, inhibition of cell bodies and fibers of passage). For optogenetics, male Wistar rats received excitatory (AAV5-EF1a-DIO -hChR2(H134R)-EYFP) or inhibitory (AAV-EF1a-DIO-eNpHR3.0-EYFP; DIO-eNpHR3.0) opsins into CNA and AAV5-EF1a-mCherry-IRES-WGA-Cre into RPO, PPT, or SubC. This enabled only CNA neurons synaptically connected to each region to express opsin. Optic cannulae for light delivery into CNA and electrodes for determining sleep were implanted. Sleep was recorded with and without blue or amber light stimulation of CNA. Separate rats received MUS or TTX into CNA prior to recording sleep. Optogenetic activation of CNA neurons projecting to RPO enhanced REM and did not alter non-REM (NREM) whereas activation of CNA neurons projecting to PPT or SubC did not significantly affect sleep. Inhibition of CNA neurons projecting to any region did not significantly alter sleep. TTX inactivation of CNA decreased REM and increased NREM whereas muscimol inactivation did not significantly alter sleep. Thus, the amygdala can regulate decreases and increases in REM, and RPO is important for CNA promotion of REM. Fibers passing through CNA, likely from the basolateral nucleus of the amygdala, also play a role in regulating sleep.
Topics: Animals; Central Amygdaloid Nucleus; Electroencephalography; Male; Microinjections; Muscimol; Optogenetics; Rats; Rats, Wistar; Sleep; Tetrodotoxin; Wakefulness
PubMed: 35131286
DOI: 10.1016/j.brainres.2022.147816 -
Journal of Neurophysiology Mar 1997The interaction of a gamma-aminobutyric acid-A (GABAA) receptor agonist and a benzodiazepine-type modulator of GABAA receptors on sleep was investigated. Low doses of...
The interaction of a gamma-aminobutyric acid-A (GABAA) receptor agonist and a benzodiazepine-type modulator of GABAA receptors on sleep was investigated. Low doses of muscimol (0.3 mg/kg) and the benzodiazepine midazolam (1.5 mg/kg) were administered alone and in combination, in random order, to eight rats. All injections were given intraperitoneally at light onset. Electroencephalogram (EEG) and electromyogram were recorded during the first 6 h post injection. Compared with vehicle, muscimol hardly affected the time spent in non-rapid eye movement sleep (non-REMS) and REMS, but significantly enhanced EEG activity in the frequency range between 2 and 6 Hz during non-REMS. Midazolam significantly increased the time spent in non-REMS, reduced EEG activity at frequencies < 12 Hz, and elevated EEG activity in most higher frequencies during this state. The combined administration of muscimol and midazolam affected non-REMS-specific EEG activity in an unexpected fashion: the effects were intermediate between those of muscimol and midazolam. These results indicate that muscimol and midazolam have dissimilar effects on EEG within non-REMS and demonstrate that midazolam does not augment but attenuates the muscimol-induced changes in sleep EEG. Our data are at variance with established mechanisms, according to which agonistic modulators would have similar effects and should potentiate the effects of GABAA agonists. The present data suggest that application of agonists and agonistic modulators of GABAA receptors causes differential net effects on sleep parameters.
Topics: Animals; Arousal; Drug Interactions; Electroencephalography; Electromyography; GABA Agonists; GABA Modulators; GABA-A Receptor Agonists; Male; Midazolam; Muscimol; Rats; Rats, Wistar; Sleep; Sleep, REM; Time Factors
PubMed: 9084625
DOI: 10.1152/jn.1997.77.3.1624 -
Addiction Biology May 2021Alcohol abuse and dependence are world-wide health problems. Most research on alcohol use focuses on the consequences of moderate to high levels of alcohol. However,...
Alcohol abuse and dependence are world-wide health problems. Most research on alcohol use focuses on the consequences of moderate to high levels of alcohol. However, even at low concentrations, alcohol is capable of producing effects in the brain that can ultimately affect behavior. The current studies seek to understand the effects of low-dose alcohol (blood alcohol levels of ≤10mM). To do so, these experiments utilize a combination of behavioral and molecular techniques to (1) assess the ability of the interoceptive effects of a low dose of alcohol to gain control over goal-tracking behavior in a Pavlovian discrimination task, (2) determine brain regional differences in cellular activity via expression of immediate early genes (IEGs), and (3) assess the role of the dentate gyrus in modulating sensitivity to the interoceptive effects of a low dose of alcohol. Here, we show that intragastric administration of a dose of 0.8 g/kg alcohol produces blood alcohol levels ≤10mM in both male and female Long-Evans rats and can readily be trained as a Pavlovian interoceptive drug cue. In rats trained on this procedure, this dose of alcohol also modulates expression of the IEGs c-Fos and Arc in brain regions known to modulate expression of alcohol interoceptive effects. Finally, pharmacological inactivation of the dentate gyrus with GABA agonists baclofen and muscimol disrupted the ability of a low dose of alcohol to serve as an interoceptive cue. Together, these findings demonstrate behavioral and molecular consequences of low-dose alcohol.
Topics: Animals; Baclofen; Behavior, Animal; Dentate Gyrus; Discrimination Learning; Ethanol; Female; Male; Muscimol; Rats; Rats, Long-Evans; Self Administration
PubMed: 33015936
DOI: 10.1111/adb.12965 -
PLoS Biology Mar 2019Neurosteroids are endogenous modulators of neuronal excitability and nervous system development and are being developed as anesthetic agents and treatments for...
Neurosteroids are endogenous modulators of neuronal excitability and nervous system development and are being developed as anesthetic agents and treatments for psychiatric diseases. While gamma amino-butyric acid Type A (GABAA) receptors are the primary molecular targets of neurosteroid action, the structural details of neurosteroid binding to these proteins remain ill defined. We synthesized neurosteroid analogue photolabeling reagents in which the photolabeling groups were placed at three positions around the neurosteroid ring structure, enabling identification of binding sites and mapping of neurosteroid orientation within these sites. Using middle-down mass spectrometry (MS), we identified three clusters of photolabeled residues representing three distinct neurosteroid binding sites in the human α1β3 GABAA receptor. Novel intrasubunit binding sites were identified within the transmembrane helical bundles of both the α1 (labeled residues α1-N408, Y415) and β3 (labeled residue β3-Y442) subunits, adjacent to the extracellular domains (ECDs). An intersubunit site (labeled residues β3-L294 and G308) in the interface between the β3(+) and α1(-) subunits of the GABAA receptor pentamer was also identified. Computational docking studies of neurosteroid to the three sites predicted critical residues contributing to neurosteroid interaction with the GABAA receptors. Electrophysiological studies of receptors with mutations based on these predictions (α1-V227W, N408A/Y411F, and Q242L) indicate that both the α1 intrasubunit and β3-α1 intersubunit sites are critical for neurosteroid action.
Topics: Animals; Binding Sites; Cell Line; Electrophysiology; Female; Flow Cytometry; Humans; Mass Spectrometry; Membrane Proteins; Molecular Docking Simulation; Muscimol; Neurotransmitter Agents; Oocytes; Receptors, GABA; Xenopus laevis
PubMed: 30845142
DOI: 10.1371/journal.pbio.3000157