Network plasticity in the medial perforant path (MPP) of adult (5-9 mo) and aged (18-20 mo) urethane-anesthetized male and female Sprague-Dawley rats was characterized. Paired pulses probed recurrent networks before and after a moderate tetanic protocol. Adult females exhibited greater EPSP-spike coupling suggesting greater intrinsic excitability than adult males. Aged rats did not differ in EPSP-spike coupling but aged females had larger spikes at high currents than males. Paired pulses suggested lower GABA-B inhibition in females. Absolute population spike measures were larger post-tetani in female rats than male rats. Relative population spike increases were greatest in adult males relative to females and to aged males. EPSP slope potentiation was detected with normalization in some post-tetanic intervals for all groups except aged males. Tetani shortened spike latency across groups. Tetani-associated NMDA-mediated burst depolarizations were larger for the first two trains in each tetanus in adult males...

Here we describe the generation and characterization of a Cre knockin mouse line which harbors a Cre insertion in the 3’UTR of the kappa opioid receptor gene (Oprk1) locus and provides genetic access to populations of kappa opioid receptor (KOR)-expressing neurons throughout the brain. Using a combination of techniques including RNA in situ hybridization and immunohistochemistry, we report that Cre is expressed with high fidelity in KOR-expressing cells throughout the brain in this mouse line. We also provide evidence that Cre insertion does not alter basal KOR function. Baseline anxiety-like behaviors and nociceptive thresholds are unaltered in Oprk1-Cre mice. Chemogenetic activation of KOR-expressing cells in the basolateral amygdala (BLAKOR cells) resulted in several sex-specific effects on anxiety-like and aversive behaviors. Activation led to decreased anxiety-like behavior on the elevated plus maze and increased sociability in female but not in male Oprk1-Cre mice. Activation of BLAKOR cells also att...

Gamma-band oscillations (GBOs) are generated by fast-spiking interneurons and are critical for cognitive functions. Abnormalities in GBOs are frequently observed in schizophrenia and bipolar disorder and are strongly correlated with cognitive impairment. However, the underlying mechanisms are poorly understood. Studying GBOs in ex vivo preparations is challenging due to high energy demands and the need for continuous oxygen delivery to the tissue. As a result, GBOs are typically studied in brain tissue from very young animals or in experimental setups that maximize oxygen supply but compromise spatial resolution. Thus, there is a limited understanding of how GBOs interact within and between different brain structures remains or in brain tissue from mature animals. To address these limitations, we have developed a novel approach for studying GBOs in ex vivo hippocampal slices from mature animals, utilizing 60-channel, perforated microelectrode arrays (pMEAs). pMEAs enhance oxygen delivery and increase spati...

Ketamine, an NMDA antagonist, is widely used in clinical settings, particularly for its promising role as a rapid antidepressant. Recently, low-dose ketamine has gained attention due to its potential therapeutic benefits. However, the effects of low-dose ketamine on brain function, particularly higher cognitive functions of primate brains, are not fully understood. In this study, we used two macaque monkeys as subjects and found that acute low-dose ketamine administration significantly impairs the ability for arbitrary visuomotor mapping, a form of associative learning essential for flexible behaviors, including executions of learned stimuli-response contingency or learning of new contingencies. We conducted in-depth analyses and identified intrinsic characteristics of these ketamine-induced functional deficits, including lowered accuracy, prolonged time for planning and movement execution, increased tendency to make errors when visual cues are changed from trial to trial, and stronger impact on the associ...

Native speakers excel at parsing continuous speech into smaller elements and entraining their neural activities to the linguistic hierarchy at different levels (e.g., syllables, phrases and sentences) to achieve speech comprehension. However, how a nonnative brain tracks hierarchical linguistic structures in second language (L2) speech comprehension and whether it relates to top-down attention and language proficiency remains elusive. Here, we applied a frequency-tagging paradigm in human adults and investigated the neural tracking responses to hierarchically organized linguistic structures (i.e., the syllabic rate of 4 Hz, the phrasal rate of 2 Hz and the sentential rate of 1 Hz) in both first language (L1) and L2 listeners when they attended to a speech stream or ignored it. We revealed disrupted neural responses to higher-order linguistic structures (i.e., phrases and sentences) for L2 listeners in which the phrasal-level tracking was functionally related to an L2 subject’s language proficiency. We also...

Interoception, the representation of the body’s internal state, serves as a foundation for emotion, motivation, and wellbeing. Yet despite its centrality in human experience, the neural mechanisms of interoceptive attention are poorly understood. The Interoceptive/Exteroceptive Attention Task (IEAT) is a novel neuroimaging paradigm that compares behavioral tracking of the respiratory cycle (Active Interoception) to tracking of a visual stimulus (Active Exteroception). Twenty-two healthy participants completed the IEAT during two separate scanning sessions (N = 44) as part of a randomized control trial of Mindful Awareness in Body-oriented Therapy (MABT). Compared to Active Exteroception, Active Interoception deactivated somatomotor and prefrontal regions. Greater self-reported interoceptive sensibility (MAIA scale) predicted sparing from deactivation within the anterior cingulate cortex (ACC) and left-lateralized language regions. The right insula—typically described as a primary interoceptive cortex—was o...

During the embryonic period, neuronal communication starts before the establishment of the synapses with alternative forms of neuronal excitability, called here Embryonic Neural Excitability (ENE). ENE has been shown to modulate the unfolding of development transcriptional programs, but the global consequences for developing organisms are not all understood. Here we monitored calcium transients in the telencephalon of zebrafish embryos as a proxy for ENE to assess the efficacy of transient pharmacological treatments to either increase or decrease ENE. Increasing or decreasing ENE at the end of the embryonic period promoted an increase or a decrease in the numbers of dopamine (DA) neurons, respectively. This plasticity of dopaminergic specification occurs in the subpallium of zebrafish larvæ at 6 dpf, within a relatively stable population of vMAT2-positive cells. Non-dopaminergic vMAT2-positive cells hence constitute an unanticipated biological marker for a reserve pool of DA neurons that can be recruited b...

Chronic nicotine results in dependence with withdrawal symptoms upon discontinuation of use, through desensitization of nicotinic acetylcholine receptors and altered cholinergic neurotransmission. Nicotine withdrawal is associated with increased whole-brain functional connectivity and decreased network modularity, however, the role of cholinergic neurons in those changes is unknown. To identify the contribution of nicotinic receptors and cholinergic regions to changes in the functional network, we analyzed the contribution of the main cholinergic regions to brain-wide activation of the immediate early-gene FOS during withdrawal in male mice and correlated these changes with the expression of nicotinic receptor mRNA throughout the brain. We show that the main functional connectivity modules included the main long-range cholinergic regions, which were highly synchronized with the rest of the brain. However, despite this hyperconnectivity they were organized into two anticorrelated networks that were separate...

Sepsis-associated encephalopathy (SAE) is a frequent severe complication of sepsis and the systemic inflammatory response syndrome, associated with high mortality and long-term neurological consequences in surviving patients. One of the main clinical signs of SAE are discontinuous sleep periods that are fragmented by frequent awakenings. Even though this brain state fragmentation strongly impacts the functionality of the nervous- and other systems, its underlying network mechanisms are still poorly understood. In this work, we therefore aim to characterize the properties and dynamics of brain oscillatory states in response to SAE in an acute rat model of sepsis induced by high dose LPS (10 mg/kg). To focus on intrinsically generated brain state dynamics, we used a urethane model that spares oscillatory activity in REM- and NREM-like sleep states. Intraperitoneal LPS injection led to a robust instability of both oscillatory states resulting in several folds more state transitions. We identified opposing shi...

Experiments that take advantage of head fixed behavioral tasks have been a staple of systems neuroscience research for half a century. More recently, rodents came to the forefront of these efforts, primarily due to the rich experimental possibilities afforded by modern genetic tools. There is however a considerable barrier to entering this field, requiring expertise in engineering, hardware- and software development, and significant time- and financial commitment. Here, we present a comprehensive, open-source hardware and software solution to implement a Head-fixed Environment for Rodent Behaviors (HERBs). Our solution provides access to three frequently used experimental frameworks (two-alternative forced choice, go-nogo, or passive sensory stimulus presentation) in a single package. The required hardware can be built at a relatively low cost compared to commercially available solutions, from off-the-shelf components. Our graphical user interface (GUI) based software provides great experimental flexibilit...