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The basolateral amygdala (BL) is a major regulator of foraging behavior. Following BL inactivation, rats become indifferent to predators. However, at odds with the view that the amygdala detects threats and generate defensive behaviors, most BL neurons have reduced firing rates during foraging and at proximity of the predator. In search of the signals determining this unexpected activity pattern, this study considered the contribution of the central medial thalamic nucleus (CMT), which sends a strong projection to BL, mostly targeting its principal neurons. Inactivation of CMT or BL with muscimol abolished the rats’ normally cautious behavior in the foraging task. Moreover, unit recordings revealed that CMT neurons showed large but heterogeneous activity changes during the foraging task, with many neurons decreasing or increasing their discharge rates, with a modest bias for the latter. A generalized linear model revealed that CMT neurons encode many of the same task variables as principal BL cells. However, the nature (inhibitory vs. excitatory) and relative magnitude of the activity modulations seen in CMT neurons differed markedly from those of principal BL cells but were very similar to those of fast-spiking BL interneurons. Together, these findings suggest that, during the foraging task, CMT inputs fire some principal BL neurons, recruiting feedback interneurons in BL, resulting in the widespread inhibition of principal BL cells.

Abstract Background: Alzheimer’s disease (AD) is a progressive multifaceted neurodegenerative disorder for which no disease-modifying treatment exists. Neuroinflammation is central to the pathology progression, with evidence suggesting that microglia-released galectin 3 (gal3) plays a pivotal role by amplifying neuroinflammation in AD. However, possible involvement of gal3 in the disruption of cognition-relevant neuronal network oscillations typical of AD remains unknown. Methods: Here, we investigate the functional implications of gal3 signaling on cognition-relevant gamma oscillations (30-80 Hz) by performing electrophysiological recordings in hippocampal area CA3 of wild-type (WT) and 5xFAD mice in vitro. Results: Gal3 application decreases gamma oscillation power and rhythmicity in an activity-dependent manner and is accompanied by impairment of cellular dynamics in fast-spiking interneurons (FSN) and pyramidal cells (PCs). We found that gal3-induced disruption is mediated by the gal3-carbohydrate-recognition domain and prevented by the gal3 inhibitor TD139, which also prevents Aβ42-induced degradation of gamma oscillations. Furthermore, we demonstrate that 5xFAD mice lacking gal3 (5xFAD-Gal3KO) exhibit WT-like gamma network dynamics.Conclusions: We report for the first time that gal3 impairs cognition-relevant neuronal network dynamics by spike-phase uncoupling of FSN inducing a network performance collapse. Moreover, our findings suggest gal3 inhibition as a potential therapeutic target to counteract the neuronal network instability typical of AD and other neurological disorders encompassing neuroinflammation and cognitive decline.

The neuromodulator acetylcholine (ACh) plays an important role in arousal, attention, vigilance, learning and memory. ACh is released during different behavioural states and affects the brain microcircuit by regulating neuronal and synaptic properties. Here, we investigated how a low concentration of ACh (30 μM) affects the intrinsic properties of electrophysiologically and morphologically identified excitatory and inhibitory neurons in layer 4 (L4) of rat barrel cortex. ACh altered the membrane potential of L4 neurons in a heterogeneous manner. Nearly all L4 regular spiking (RS) neurons responded to bath-application of ACh with a M4 muscarinic ACh receptor-mediated hyperpolarisation. In contrast, in the majority of L4 fast spiking (FS) and non-fast spiking (nFS) interneurons 30 μM ACh induced a depolarisation while the remainder showed a hyperpolarisation or no response. The ACh-induced depolarisation of L4 FS interneurons was much weaker than that in L4 nFS interneurons. There was no clear difference in the response to ACh for three morphological subtypes of L4 FS interneurons. However, in four morpho-electrophysiological subtypes of L4 nFS interneurons, VIP+-like interneurons showed the strongest ACh-induced depolarisation; occasionally, even action potential (AP) firing was elicited. The ACh-induced depolarisation in L4 FS interneurons was exclusively mediated by M1 muscarinic ACh receptors; in L4 nFS interneurons it was mainly mediated by M1 and/or M3/5 muscarinic ACh receptors. In a subset of L4 nFS interneurons, a co-operative activation of nicotinic ACh receptors was also observed. The present study demonstrates that low-concentrations of ACh affect the different L4 neurons types in a cell-type specific way. These effects result from a specific expression of different muscarinic and/or nicotinic ACh receptors on the somatodendritic compartments of L4 neurons. This suggests that even at low concentrations ACh may tune the excitability of L4 excitatory and inhibitory neurons and their synaptic microcircuits differentially depending on the behavioural state during which ACh is released.

The hippocampal gamma oscillation is important for cognitive function, and its deficit is related to cognitive impairment in Alzheimer’s disease (AD). Recently, it has been recognized that post-translational modification via histone acetylation is a fundamental molecular mechanism for regulating synaptic plasticity and cognitive function. However, little is known regarding the regulation of hippocampal gamma oscillation by histone acetylation. We investigated whether histone acetylation regulated kainate-induced gamma oscillations and their important regulator, fast-spiking interneurons, using acute hippocampal slices of AD model mice (PSAPP transgenic mice). We found a decrease in kainate-induced gamma oscillations in slices from PSAPP mice, accompanied with the increased activity of fast spiking interneurons in basal state and the decreased activity in activated state. The histone deacetylase (HDAC) inhibitor (SAHA, named vorinostat) restored deficits of gamma oscillation in PSAPP mice, accompanied with rescue of activity of fast spiking interneurons in basal and activated state. The effect of SAHA was different from that of the clinical AD drug donepezil, which rescued only function of fast spiking interneurons in basal state. Besides, activator of nuclear receptor family 4a (NR4a) receptor (cytosporone B), as one of the epigenetic modification related to HDAC inhibition, rescued the deficits in gamma oscillations in PSAPP mice. These results suggested a novel mechanism in which HDAC inhibition improved impairment of gamma oscillations in PSAPP mice by restoring the activity of fast spiking interneurons both in basal and activated state. The reversal of gamma oscillation deficits by HDAC inhibition and/or NR4a activation appears to be a potential therapeutic target for treating cognitive impairment in AD patients.

Fast oscillations in cortical circuits critically depend on GABAergic interneurons. Which interneuron types and populations can drive different cortical rhythms, however, remains unresolved and may depend on brain state. Here, we measured the sensitivity of different GABAergic interneurons in prefrontal cortex under conditions mimicking distinct brain states. While fast-spiking neurons always exhibited a wide bandwidth of around 400 Hz, the response properties of spike-frequency adapting interneurons switched with the background input’s statistics. Slowly fluctuating background activity, as typical for sleep or quiet wakefulness, dramatically boosted the neurons’ sensitivity to gamma and ripple frequencies. We developed a time-resolved dynamic gain analysis and revealed rapid sensitivity modulations that enable neurons to periodically boost gamma oscillations and ripples during specific phases of ongoing low-frequency oscillations. This mechanism predicts these prefrontal interneurons to be exquisitely sensitive to high-frequency ripples, especially during brain states characterized by slow rhythms, and to contribute substantially to theta-gamma cross-frequency coupling.

AbstractWe interrogated prefrontal circuit function in mice lacking Disrupted-in-schizophrenia-1 (Disc1-mutant mice), a risk factor for psychiatric disorders. Single-unit recordings in awake mice revealed reduced average firing rates of fast-spiking interneurons (INTs), including optogenetically identified parvalbumin-positive cells, and a lower proportion of INTs phase-coupled to ongoing gamma oscillations. Moreover, we observed decreased spike transmission efficacy at local pyramidal cell (PYR)-INT connections in vivo, suggesting a reduced excitatory effect of local glutamatergic inputs as a potential mechanism of lower INT rates. On the network level, impaired INT function resulted in altered activation of PYR assemblies: While assembly activations were observed equally often, the expression strength of individual assembly patterns was significantly higher in Disc1-mutant mice. Our data thus reveal a role of Disc1 in shaping the properties of prefrontal assembly patterns by setting prefrontal INT responsiveness to glutamatergic drive.

Traumatic brain injury (TBI) is a leading cause of neurologic disability; the most common deficits affect prefrontal cortex-dependent functions such as attention, working memory, social behavior, and mental flexibility. Despite this prevalence, little is known about the pathophysiology that develops in frontal cortical microcircuits after TBI. We investigated if alterations in subtype-specific inhibitory circuits are associated with cognitive inflexibility in a mouse model of frontal lobe contusion that recapitulates aberrant mental flexibility as measured by deficits in rule reversal learning. Using patch clamp recordings and optogenetic stimulation, we identified selective vulnerability in the non-fast spiking, somatostatin-expressing (SOM+) subtype of inhibitory neurons in layer V of the orbitofrontal cortex (OFC) two months after injury. These neurons exhibited reduced intrinsic excitability and a decrease in their synaptic output onto pyramidal neurons. By contrast, fast spiking, parvalbumin-expressing (PV+) interneurons did not show changes in intrinsic excitability or synaptic output. Impairments in SOM+ inhibitory circuit function were also associated with network hyperexcitability. These findings provide evidence for selective disruptions within specific inhibitory microcircuits that may guide the development of novel therapeutics for TBI.

The voltage-gated K+ channels Kv3.1 display fast activation and deactivation kinetics and are known to have a crucial contribution to the fast-spiking phenotype of certain neurons. AahG50, as a natural product extracted from Androctonus australis hector venom, inhibits selectively Kv3.1 channels. In the present study, we focused on the biochemical and pharmacological characterization of the component in AahG50 scorpion venom that potently and selectively blocks the Kv3.1 channels. We used a combined optimization through advanced biochemical purification and patch-clamp screening steps to characterize the peptide in AahG50 active on Kv3.1 channels. We described the inhibitory effect of a toxin on Kv3.1 unitary current in black lipid bilayers. In silico, docking experiments are used to study the molecular details of the binding. We identified the first scorpion venom peptide inhibiting Kv3.1 current at 170 nM. This toxin is the alpha-KTx 15.1, which occludes the Kv3.1 channel pore by means of the lysine 27 lateral chain. This study highlights, for the first time, the modulation of the Kv3.1 by alpha-KTx 15.1, which could be an interesting starting compound for developing therapeutic biomolecules against Kv3.1-associated diseases.