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The assessment of consciousness states, especially distinguishing minimally conscious states (MCS) from unresponsive wakefulness states (UWS), constitutes a pivotal role in clinical therapies. Despite that numerous neural signatures of consciousness have been proposed, the effectiveness and reliability of such signatures for clinical consciousness assessment still remains an intense debate. Through a comprehensive review of the literature, inconsistent findings are observed about the effectiveness of diverse neural signatures. Notably, the majority of existing studies have evaluated neural signatures on a limited number of subjects (usually below 30), which may result in uncertain conclusions due to small data bias. This study presents a systematic evaluation of neural signatures with large‐scale clinical resting‐state electroencephalography (EEG) signals containing 99 UWS, 129 MCS, 36 emergence from the minimally conscious state, and 32 healthy subjects (296 total) collected over 3 years. A total of 380 EEG‐based metrics for consciousness detection, including spectrum features, nonlinear measures, functional connectivity, and graph‐based measures, are summarized and evaluated. To further mitigate the effect of data bias, the evaluation is performed with bootstrap sampling so that reliable measures can be obtained. The results of this study suggest that relative power in alpha and delta serve as dependable indicators of consciousness. With the MCS group, there is a notable increase in the phase lag index‐related connectivity measures and enhanced functional connectivity between brain regions in comparison to the UWS group. A combination of features enables the development of an automatic detector of conscious states. [ABSTRACT FROM AUTHOR]

Dysfunction in the prefrontal cortex is commonly implicated in anxiety disorders, but the mechanisms remain unclear. Approach-avoidance conflict tasks have been extensively used in animal research to better understand how changes in neural activity within the prefrontal cortex contribute to avoidance behaviors, which are believed to play a major role in the maintenance of anxiety disorders. In this article, we first review studies utilizing in vivo electrophysiology to reveal the relationship between changes in neural activity and avoidance behavior in rodents. We then review recent studies that take advantage of optical and genetic techniques to test the unique contribution of specific prefrontal cortex circuits and cell types to the control of anxiety-related avoidance behaviors. This new body of work reveals that behavior during approach-avoidance conflict is dynamically modulated by individual cell types, distinct neural pathways, and specific oscillatory frequencies. The integration of these different pathways, particularly as mediated by interactions between excitatory and inhibitory neurons, represents an exciting opportunity for the future of understanding anxiety. [ABSTRACT FROM AUTHOR]

Author(s): Yousheng Shu; Andrea Hasenstaub; David A. McCormick (corresponding author) The vast majority of synaptic connections onto neurons in the cerebral cortex arise from other cortical neurons, both excitatory and [...]

Chronic inflammation in liver induces insulin resistance systemically and in other tissues, including the skeletal muscle (SM); however, the underlying mechanisms remain largely unknown. RNA sequencing of primary hepatocytes from wild-type mice fed long-term high-fat diet (HFD), which have severe chronic inflammation and insulin resistance revealed that the expression of hepatokine endoplasmic reticulum aminopeptidase 1 (ERAP1) was upregulated by a HFD. Increased ERAP1 levels were also observed in interferon-γ-treated primary hepatocytes. Furthermore, hepatic ERAP1 overexpression attenuated systemic and SM insulin sensitivity, whereas hepatic ERAP1 knockdown had the opposite effects, with corresponding changes in serum ERAP1 levels. Mechanistically, ERAP1 functions as an antagonist-like factor, which interacts with β2 adrenergic receptor (ADRB2) and reduces its expression by decreasing ubiquitin-specific peptidase 33-mediated deubiquitination and thereby interrupts ADRB2-stimulated insulin signaling in the SM. The findings of this study indicate ERAP1 is an inflammation-induced hepatokine that impairs SM insulin sensitivity. Its inhibition may provide a therapeutic strategy for insulin resistance-related diseases, such as type 2 diabetes. [ABSTRACT FROM AUTHOR]

Prefrontal cortical GABAergic interneurons (INs) and their innervations are essential for the execution of complex behaviors such as working memory, social behavior, and fear expression. These behavior regulations are highly dependent on primary long-range afferents originating from the subcortical structures such as mediodorsal thalamus (MD), ventral hippocampus (vHPC), and basolateral amygdala (BLA). In turn, the regulatory effects of these inputs are mediated by activation of parvalbumin-expressing (PV) and/or somatostatin expressing (SST) INs within the prefrontal cortex (PFC). Here we review how each of these long-range afferents from the MD, vHPC, or BLA recruits a subset of the prefrontal interneuron population to exert precise control of specific PFC-dependent behaviors. Specifically, we first summarize the anatomical connections of different long-range inputs formed on prefrontal GABAergic INs, focusing on PV versus SST cells. Next, we elaborate on the role of prefrontal PV- and SST- INs in regulating MD afferents-mediated cognitive behaviors. We also examine how prefrontal PV- and SST- INs gate vHPC afferents in spatial working memory and fear expression. Finally, we discuss the possibility that prefrontal PV-INs mediate fear conditioning, predominantly driven by the BLA-mPFC pathway. This review will provide a broad view of how multiple long-range inputs converge on prefrontal interneurons to regulate complex behaviors and novel future directions to understand how PFC controls different behaviors. [ABSTRACT FROM AUTHOR]

Maternal immune activation (MIA) and juvenile social isolation (SI) are two most prevalent and widely accepted environmental insults that could increase the propensity of psychiatric illnesses. Using a two-hit mouse model, we examined the impact of the combination of these two factors on animal behaviors, neuronal excitability and expressions of voltage-gated sodium (Nav) and small conductance calcium-activated potassium (SK) channels in the prefrontal cortex (PFC). We found that MIA-SI induced a number of schizophrenia-related behavioral deficits. Patch clamp recordings revealed alterations in electrophysiological properties of PFC layer-5 pyramidal cells, including hyperpolarized resting membrane potential (RMP), increased input resistance and enhanced medium after-hyperpolarization (mAHP). MIA-SI also increased the ratio of the maximal slope of somatodendritic potential to the peak slope of action potential upstroke, indicating a change in perisomatic Nav availability. Consistently, MIA-SI significantly increased the expression level of Nav1.2 and SK3 channels that contribute to the somatodendritic potential and the mAHP, respectively. Together, these changes may alter neuronal signaling in the PFC and behavioral states, representing a molecular imprint of environmental insults associated with neuropsychiatric illnesses. [ABSTRACT FROM AUTHOR]

Spiking activities of midbrain dopaminergic neurons are critical for key brain functions including motor control and affective behaviors. Voltage-gated Na+ channels determine neuronal excitability and action potential (AP) generation. Previous studies on dopaminergic neuron excitability mainly focused on Na+ channels at the somatodendritic compartments. Properties of axonal Na+ channels, however, remain largely unknown. Using patch-clamp recording from somatic nucleated patches and isolated axonal blebs from the axon initial segment (AIS) of dopaminergic neurons in mouse midbrain slices, we found that AIS channel density is approximately 4–9 fold higher than that at the soma. Similar voltage dependence of channel activation and inactivation was observed between somatic and axonal channels in both SNc and VTA cells, except that SNc somatic channels inactivate at more hyperpolarized membrane potentials (V m). In both SNc and VTA, axonal channels take longer time to inactivate at a subthreshold depolarization V m level, but are faster to recover from inactivation than somatic channels. Moreover, we found that immunosignals of Nav1.2 accumulate at the AIS of dopaminergic neurons. In contrast, Nav1.1 and Nav1.6 immunosignals are not detectible. Together, our results reveal a high density of Na+ channels at the AIS and their molecular identity. In general, somatic and axonal channels of both SNc and VTA dopaminergic neurons share similar biophysical properties. The relatively delayed inactivation onset and faster recovery from inactivation of axonal Na+ channels may ensure AP initiation at high frequencies and faithful signal conduction along the axon. [ABSTRACT FROM AUTHOR]

Summary A critical step in understanding the neural basis of human cognitive functions is to identify neuronal types in the neocortex. In this study, we performed whole-cell recording from human cortical slices and found a distinct subpopulation of neurons with intrinsic persistent activity that could be triggered by single action potentials (APs) but terminated by bursts of APs. This persistent activity was associated with a depolarizing plateau potential induced by the activation of a persistent Na + current. Single-cell RT-PCR revealed that these neurons were inhibitory interneurons. This type of neuron was found in different cortical regions, including temporal, frontal, occipital, and parietal cortices in human and also in frontal and temporal lobes of nonhuman primate but not in rat cortical tissues, suggesting that it could be unique to primates. The characteristic persistent activity in these inhibitory interneurons may contribute to the regulation of pyramidal cell activity and participate in cortical processing. [ABSTRACT FROM AUTHOR]

Enhanced beta oscillations within the cortico-basal ganglia-thalamic (CBT) network are correlated with motor deficits in Parkinson's disease (PD), whose generation has been associated recently with amplified network dynamics in the striatum. However, how distinct striatal cell subtypes interact to orchestrate beta oscillations remains largely unknown. Here, we show that optogenetic suppression of dopaminergic control over the dorsal striatum (DS) elevates the power of local field potentials (LFPs) selectively at beta band (12–25 Hz), accompanied by impairments in locomotion. The amplified beta power originates from a striatal loop driven by somatostatin-expressing (SOM) interneurons and constituted by choline acetyltransferase (ChAT)-expressing interneurons and dopamine D2 receptor (D2R)-expressing medium spiny neurons (iMSNs). Moreover, closed-loop intervention selectively targeting striatal iMSNs or ChATs diminishes beta oscillations and restores motor function. Thus, we reveal a striatal microcircuit motif that underlies beta oscillation generation and accompanied motor deficits upon perturbation of dopaminergic control over the striatum. [Display omitted] • Inhibition of DANs selectively enhances beta oscillations and produces motor deficits • SOMs function as the downstream effectors for DANs in beta oscillation generation • The amplified beta power originates from a striatal SOM-driven ChAT-iMSN loop • Closed-loop inhibition iMSNs or ChATs reduces beta power and improves motor deficits Qian et al. demonstrate that photoinhibition of substantia nigra pars compacta (SNc) dopaminergic terminals in striatum enhances beta oscillations, accompanied by impairment in locomotion. Specifically, the enhancement in beta power originates from a loop circuit driven by somatostatin interneurons and constituted by cholinergic interneuron and D2R medium spiny neurons. [ABSTRACT FROM AUTHOR]

: Sodium channels add variety to inhibitory interneurons Different populations of inhibitory interneurons in the cerebral cortex express distinct subtypes of sodium channels, resulting in diverse action potential thresholds and network excitability. [ABSTRACT FROM AUTHOR]

GABAA receptors distributed in somatodendritic compartments play critical roles in regulating neuronal activities, including spike timing and firing pattern; however, the properties and functions of GABAA receptors at the axon are still poorly understood. By recording from the cut end (bleb) of the main axon trunk of layer –5 pyramidal neurons in prefrontal cortical slices, we found that currents evoked by GABA iontophoresis could be blocked by picrotoxin, indicating the expression of GABAA receptors in axons. Stationary noise analysis revealed that single-channel properties of axonal GABAA receptors were similar to those of somatic receptors. Perforated patch recording with gramicidin revealed that the reversal potential of the GABA response was more negative than the resting membrane potential at the axon trunk, suggesting that GABA may hyperpolarize the axonal membrane potential. Further experiments demonstrated that the activation of axonal GABAA receptors regulated the amplitude and duration of action potentials (APs) and decreased the AP-induced Ca2+ transients at the axon. Together, our results indicate that the waveform of axonal APs and the downstream Ca2+ signals are modulated by axonal GABAA receptors. [ABSTRACT FROM AUTHOR]

Summary: Temporal precision in spike timing is important in cortical function, interactions, and plasticity. We found that, during periods of recurrent network activity (UP states), cortical pyramidal cells in vivo and in vitro receive strong barrages of both excitatory and inhibitory postsynaptic potentials, with the inhibitory potentials showing much higher power at all frequencies above approximately 10 Hz and more synchrony between nearby neurons. Fast-spiking inhibitory interneurons discharged strongly in relation to higher-frequency oscillations in the field potential in vivo and possess membrane, synaptic, and action potential properties that are advantageous for transmission of higher-frequency activity. Intracellular injection of synaptic conductances having the characteristics of the recorded EPSPs and IPSPs reveal that IPSPs are important in controlling the timing and probability of action potential generation in pyramidal cells. Our results support the hypothesis that inhibitory networks are largely responsible for the dissemination of higher-frequency activity in cortex. [Copyright &y& Elsevier]