Experience-dependent information routing through the basolateral amygdala shapes behavioral outcomes.

It is well established that the basolateral amygdala (BLA) is an emotional processing hub that governs a diverse repertoire of behaviors. Selective engagement of a heterogeneous cell population in the BLA is thought to contribute to this flexibility in behavioral outcomes. However, whether this process is impacted by previous experiences that influence emotional processing remains unclear. Here we demonstrate that previous positive (enriched environment [EE]) or negative (chronic unpredictable stress [CUS]) experiences differentially influence the activity of populations of BLA principal neurons projecting to either the nucleus accumbens core or bed nucleus of the stria terminalis. Chemogenetic manipulation of these projection-specific neurons can mimic or occlude the effects of CUS and EE on behavioral outcomes to bidirectionally control avoidance behaviors and stress-induced helplessness. These data demonstrate that previous experiences influence the responsiveness of projection-specific BLA principal neurons, biasing information routing through the BLA, to drive divergent behavioral outcomes.

Sustained Inhibition of GABA-AT by OV329 Enhances Neuronal Inhibition and Prevents Development of Benzodiazepine Refractory Seizures.

γ-Aminobutyric acid (GABA) is the principal inhibitory neurotransmitter in the adult brain which mediates its rapid effects on neuronal excitability via ionotropic GABAA receptors. GABA levels in the brain are critically dependent upon GABA-aminotransferase (GABA-AT) which promotes its degradation. Vigabatrin, a low-affinity GABA-AT inhibitor, exhibits anticonvulsant efficacy, but its use is limited due to cumulative ocular toxicity. OV329 is a rationally designed, next-generation GABA-AT inhibitor with enhanced potency. We demonstrate that sustained exposure to OV329 in mice reduces GABA-AT activity and subsequently elevates GABA levels in the brain. Parallel increases in the efficacy of GABAergic inhibition were evident, together with elevations in electroencephalographic delta power. Consistent with this, OV329 exposure reduced the severity of status epilepticus and the development of benzodiazepine refractory seizures. Thus, OV329 may be of utility in treating seizure disorders and associated pathologies that result from neuronal hyperexcitability.

Loss of PV interneurons in the BLA contributes to altered network and behavioral states in chronically epileptic mice.

Psychiatric disorders, including anxiety and depression, are highly comorbid in people with epilepsy. However, the mechanisms mediating the shared pathophysiology are currently unknown. There is considerable evidence implicating the basolateral amygdala (BLA) in the network communication of anxiety and fear, a process demonstrated to involve parvalbumin-positive (PV) interneurons. The loss of PV interneurons has been well described in the hippocampus of chronically epileptic mice and in postmortem human tissue of patients with temporal lobe epilepsy (TLE). We hypothesize that a loss of PV interneurons in the BLA may contribute to comorbid mood disorders in epilepsy. To test this hypothesis, we employed a ventral intrahippocampal kainic acid (vIHKA) model of chronic epilepsy in mice, which exhibits profound behavioral deficits associated with chronic epilepsy. We demonstrate a loss of PV interneurons and dysfunction of remaining PV interneurons in the BLA of chronically epileptic mice. Further, we demonstrate altered principal neuron function and impaired coordination of BLA network and behavioral states in chronically epileptic mice. To determine whether these altered network and behavioral states were due to the loss of PV interneurons, we ablated a similar percentage of PV interneurons observed in chronically epileptic mice by stereotaxically injecting AAV-Flex-DTA into the BLA of PV-Cre mice. Loss of PV interneurons in the BLA is sufficient to alter behavioral states, inducing deficits in fear learning and recall of fear memories. These data suggest that compromised inhibition in the BLA in chronically epileptic mice contributes to behavioral deficits, suggesting a novel mechanism contributing to comorbid anxiety and epilepsy. Significance Statement: Psychiatric illnesses and epilepsy are highly comorbid and negatively impact the quality of life of people with epilepsy. The pathophysiological mechanisms mediating the bidirectional relationship between mood disorders and epilepsy remain unknown and, therefore, treatment options remain inadequate. Here we demonstrate a novel mechanism, involving the loss of PV interneurons in the BLA, leading to a corruption of network and behavioral states in mice. These findings pinpoint a critical node and demonstrate a novel cellular and circuit mechanism involved in the comorbidity of psychiatric illnesses and epilepsy.

Experience-dependent information routing through the basolateral amygdala.

The basolateral amygdala (BLA) is an emotional processing hub and is well-established to influence both positive and negative valence processing. Selective engagement of a heterogeneous cell population in the BLA is thought to contribute to this flexibility in valence processing. However, how this process is impacted by previous experiences which influence valence processing is unknown. Here we demonstrate that previous positive (EE) or negative (chronic unpredictable stress) experiences differentially influence the activity of specific populations of BLA principal neurons projecting to either the nucleus accumbens core or bed nucleus of the stria terminalis. Using chemogenetic manipulation of these projection-specific neurons we can mimic or occlude the effects of chronic unpredictable stress or enriched environment on valence processing to bidirectionally control avoidance behaviors and stress-induced helplessness. These data demonstrate that previous experiences influence the responsiveness of projection-specific BLA principal neurons, biasing information routing through the BLA, to govern valence processing.

Influence of chronic stress on network states governing valence processing: Potential relevance to the risk for psychiatric illnesses.

Stress is a major risk factor for psychiatric illnesses and understanding the mechanisms through which stress disrupts behavioral states is imperative to understanding the underlying pathophysiology of mood disorders. Both chronic stress and early life stress alter valence processing, the process of assigning value to sensory inputs and experiences (positive or negative), which determines subsequent behavior and is essential for emotional processing and ultimately survival. Stress disrupts valence processing in both humans and preclinical models, favoring negative valence processing and impairing positive valence processing. Valence assignment involves neural computations performed in emotional processing hubs, including the amygdala, prefrontal cortex, and ventral hippocampus, which can be influenced by neuroendocrine mediators. Oscillations within and between these regions are critical for the neural computations necessary to perform valence processing functions. Major advances in the field have demonstrated a role for oscillatory states in valence processing under physiological conditions and emerging studies are exploring how these network states are altered under pathophysiological conditions and impacted by neuroendocrine factors. The current review highlights what is currently known regarding the impact of stress and the role of neuroendocrine mediators on network states and valence processing. Further, we propose a model in which chronic stress alters information routing through emotional processing hubs, resulting in a facilitation of negative valence processing and a suppression of positive valence processing.

Allopregnanolone Mediates Affective Switching Through Modulation of Oscillatory States in the Basolateral Amygdala.

BACKGROUND: Brexanolone (allopregnanolone) was recently approved by the Food and Drug Administration for the treatment of postpartum depression, demonstrating long-lasting antidepressant effects. Despite our understanding of the mechanism of action of neurosteroids as positive allosteric modulators of GABAA (gamma-aminobutyric acid A) receptors, we still do not fully understand how allopregnanolone exerts persistent antidepressant effects. METHODS: We used electroencephalogram recordings in rats and humans along with local field potential, functional magnetic resonance imaging, and behavioral tests in mice to assess the impact of neurosteroids on network states in brain regions implicated in mood and used optogenetic manipulations to directly examine their relationship to behavioral states. RESULTS: We demonstrated that allopregnanolone and synthetic neuroactive steroid analogs with molecular pharmacology similar to allopregnanolone (SGE-516 [tool compound] and zuranolone [SAGE-217, investigational compound]) modulate oscillations across species. We further demonstrated a critical role for interneurons in generating oscillations in the basolateral amygdala (BLA) and a role for δ-containing GABAA receptors in mediating the ability of neurosteroids to modulate network and behavioral states. Allopregnanolone in the BLA enhances BLA high theta oscillations (6-12 Hz) through δ-containing GABAA receptors, a mechanism distinct from other GABAA positive allosteric modulators, such as benzodiazepines, and alters behavioral states. Treatment with the allopregnanolone analog SGE-516 protects mice from chronic stress-induced disruption of network and behavioral states, which is correlated with the modulation of theta oscillations in the BLA. Optogenetic manipulation of the network state influences the behavioral state after chronic unpredictable stress. CONCLUSIONS: Our findings demonstrate a novel molecular and cellular mechanism mediating the well-established anxiolytic and antidepressant effects of neuroactive steroids.

Network Dysfunction in Comorbid Psychiatric Illnesses and Epilepsy.

The episodic nature of both epilepsy and psychiatric illnesses suggests that the brain switches between healthy and pathological states. The most obvious example of transitions between network states related to epilepsy is the manifestation of ictal events. In addition to seizures, there are more subtle changes in network communication within and between brain regions, which we propose may contribute to psychiatric illnesses associated with the epilepsies. This review will highlight evidence supporting aberrant network activity associated with epilepsy and the contribution to cognitive impairments and comorbid psychiatric illnesses. Further, we discuss potential mechanisms mediating the network dysfunction associated with comorbidities in epilepsy, including interneuron loss and hypothalamic-pituitary-adrenal axis dysfunction. Conceptually, it is necessary to think beyond ictal activity to appreciate the breadth of network dysfunction contributing to the spectrum of symptoms associated with epilepsy, including psychiatric comorbidities.

Presynaptic mGluRs Control the Duration of Endocannabinoid-Mediated DSI.

GABA synapses in the brain undergo depolarization-induced suppression of inhibition (DSI) that requires activation of presynaptic cannabinoid type 1 receptors (CB1Rs). The brevity of DSI, lasting ∼1 min in most brain regions, has been ascribed to the transient production of 2-arachidonoylglycerol (2-AG). Here, we propose that the duration of DSI is controlled by heterologous interactions between presynaptic mGluRs and CB1Rs. By examining GABA synapses on parvocellular corticotropin-releasing hormone-expressing neurons in the paraventricular nucleus of the hypothalamus (PVN) of male and female mice, we show that DSI decays quickly in experimental conditions in which both GABA and glutamate are released from adjacent nerve terminals. Pharmacological inhibition of group I mGluRs prolongs DSI, whereas prior activation of mGluRs inhibits DSI, collectively suggesting that group I mGluRs quench presynaptic CB1R signaling. When photostimulation of genetically identified terminals is used to release only GABA, CB1R-dependent DSI persists for many minutes. Under the same conditions, activation of group I mGluRs reestablishes classical, transient DSI. The long-lasting DSI observed when GABA synapses are independently recruited functionally uncouples inhibitory input to PVN neurons. These observations suggest that heterologous interactions between mGluRs and CB1Rs control the temporal window of DSI at GABA synapses, providing evidence for a powerful new way to affect functional circuit connectivity in the brain.SIGNIFICANCE STATEMENT Postsynaptic depolarization liberates endocannabinoids, resulting in a rapid and transient decrease in release probability at GABA synapses. We discovered that mGluRs control the duration of depolarization-induced suppression of inhibition (DSI), most likely through heterologous desensitization of cannabinoid type 1 receptors by presynaptic mGluR5 By shortening the duration of DSI, mGluRs control the temporal window for retrograde signaling at GABA synapses. Physiological or pathological changes that affect glutamate spillover may profoundly affect network excitability by shifting the duration of cannabinoid inhibition at GABA synapses.

Balancing tonic and phasic inhibition in hypothalamic corticotropin-releasing hormone neurons.

KEY POINTS: GABA transporter (GAT) blockade recruits extrasynaptic GABAA receptors (GABAA Rs) and amplifies constitutive presynaptic GABAB R activity. Extrasynaptic GABAA Rs contribute to a tonic current. Corticosteroids increase the tonic current mediated by extrasynaptic GABAA Rs. ABSTRACT: Corticotropin-releasing hormone (CRH) neurons in the paraventricular nucleus of the hypothalamus (PVN) are integratory hubs that regulate the endocrine response to stress. GABA inputs provide a basal inhibitory tone that constrains this system and circulating glucocorticoids (CORT) are important feedback controllers of CRH output. Surprisingly little is known about the direct effects of CORT on GABA synapses in PVN. Here we used whole-cell patch clamp recordings from CRH neurons in mouse hypothalamic brain slices to examine the effects of CORT on synaptic and extrasynaptic GABA signalling. We show that GABA transporters (GATs) limit constitutive activation of presynaptic GABAB receptors and ensure high release probability at GABA synapses. GATs in combination with GABAB receptors also curtail extrasynaptic GABAA R signalling. CORT has no effect on synaptic GABA signalling, but increases extrasynaptic GABA tone through upregulation of postsynaptic GABAA receptors. These data show that efficient GABA clearance and autoinhibition control the balance between synaptic (phasic) and extrasynaptic (tonic) inhibition in PVN CRH neurons. This balance is shifted towards increased extrasynaptic inhibition by CORT.

Electrical coupling between Aplysia bag cell neurons: characterization and role in synchronous firing.

In neuroendocrine cells, hormone release often requires a collective burst of action potentials synchronized by gap junctions. This is the case for the electrically coupled bag cell neurons in the reproductive system of the marine snail, Aplysia californica. These neuroendocrine cells are found in two clusters, and fire a synchronous burst, called the afterdischarge, resulting in neuropeptide secretion and the triggering of ovulation. However, the physiology and pharmacology of the bag cell neuron electrical synapse are not completely understood. As such, we made dual whole cell recordings from pairs of electrically coupled cultured bag cell neurons. The junctional current was nonrectifying and not influenced by postsynaptic voltage. Furthermore, junctional conductance was voltage independent and, not surprisingly, strongly correlated with coupling coefficient magnitude. The electrical synapse also acted as a low-pass filter, although under certain conditions, electrotonic potentials evoked by presynaptic action potentials could drive postsynaptic spikes. If coupled neurons were stimulated to spike simultaneously, they presented a high degree of action potential synchrony compared with not-coupled neurons. The electrical synapse failed to pass various intracellular dyes, but was permeable to Cs(+), and could be inhibited by niflumic acid, meclofenamic acid, or 5-nitro-2-(3-phenylpropylamino)benzoic acid. Finally, extracellular and sharp-electrode recording from the intact bag cell neuron cluster showed that these pharmacological uncouplers disrupted both electrical coupling and afterdischarge generation in situ. Thus electrical synapses promote bag cell neuron firing synchrony and may allow for electrotonic spread of the burst through the network, ultimately contributing to propagation of the species.