RESUMO
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.
Assuntos
Complexo Nuclear Basolateral da Amígdala , Comportamento Animal , Animais , Complexo Nuclear Basolateral da Amígdala/fisiologia , Masculino , Neurônios/fisiologia , Camundongos , Estresse Psicológico , Núcleo Accumbens/fisiologia , Camundongos Endogâmicos C57BL , Núcleos Septais/fisiologiaRESUMO
Neurosteroids have been implicated in the pathophysiology of post-traumatic stress disorder (PTSD). Allopregnanolone is reduced in subsets of individuals with PTSD and has been explored as a novel treatment strategy. Both direct trauma exposure and witnessed trauma are risk factors for PTSD; however, the role of neurosteroids in the behavioral outcomes of these unique experiences has not been explored. Here, we investigate whether observational fear is associated with a reduced capacity for endogenous neurosteroidogenesis and the relationship with behavioral outcomes. We demonstrated that mice directly subjected to a threat (foot shocks) and those witnessing the threat have decreased plasma levels of allopregnanolone. The expression of a key enzyme involved in endogenous neurosteroid synthesis, 5α-reductase type 2, is decreased in the basolateral amygdala, which is a major emotional processing hub implicated in PTSD. We demonstrated that genetic knockdown or pharmacological inhibition of 5α-reductase type 2 exaggerates the behavioral expression of fear in response to witnessed trauma, whereas oral treatment with an exogenous, synthetic neuroactive steroid gamma-aminobutyric acid-A receptor positive allosteric modulator with molecular pharmacology similar to allopregnanolone (SGE-516 [tool compound]) decreased the behavioral response to observational fear. These data implicate impaired endogenous neurosteroidogenesis in the pathophysiology of threat exposure, both direct and witnessed. Further, these data suggest that treatment with exogenous 5α-reduced neurosteroids or targeting endogenous neurosteroidogenesis may be beneficial for the treatment of individuals with PTSD, whether resulting from direct or witnessed trauma.
Assuntos
Neuroesteroides , Animais , Camundongos , Pregnanolona/metabolismo , Receptores de GABA-A/metabolismo , Medo/fisiologia , Emoções , Colestenona 5 alfa-Redutase/metabolismoRESUMO
Previously we demonstrated that intra-hippocampal infusion of purified, Semaphorin 4D (Sema4D) extracellular domain (ECD) into the mouse hippocampus rapidly promotes formation of GABAergic synapses and decreases seizure susceptibility in mice. Given the relatively fast action of Sema4D treatment revealed by these studies, we sought to determine the time course of Sema4D treatment on hippocampal network activity using an acute hippocampal slice preparation. We performed long-term extracellular recordings from area CA1 encompassing a 2-hour application of Sema4D and found that hippocampal excitation is suppressed for hours following treatment. We also asked if Sema4D treatment could ameliorate seizures in an acute seizure model: the kainic acid (KA) mouse model. We demonstrate that Sema4D treatment delays and suppresses ictal activity, delays the transition to Status Epilepticus (SE), and lessens the severity of SE. Lastly, we sought to explore alternative methods of Sema4D delivery to hippocampus and thus created an Adeno Associated Virus expressing the ECD of Sema4D. Our data reveal that virally delivered, chronically overexpressed Sema4D-ECD promotes GABAergic synapse formation and suppresses ictal activity and progression to SE. These results provide proof of concept that viral delivery of Sema4D is an efficacious and promising delivery method to abate epileptiform activity and progression to SE.
Assuntos
Semaforinas , Estado Epiléptico , Camundongos , Animais , Estado Epiléptico/induzido quimicamente , Estado Epiléptico/tratamento farmacológico , Antígenos CD , Convulsões/induzido quimicamente , Convulsões/tratamento farmacológico , Semaforinas/metabolismo , Hipocampo/metabolismoRESUMO
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.
Assuntos
Emoções , Transtornos Mentais , Humanos , Emoções/fisiologia , Tonsila do Cerebelo/fisiologia , Córtex Pré-Frontal , HipocampoRESUMO
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.
RESUMO
BACKGROUND: Chronic stress is a major risk factor for psychiatric illnesses, including depression. However, the pathophysiological mechanisms whereby stress leads to mood disorders remain unclear. Allopregnanolone acts as a positive allosteric modulator preferentially on δ subunit-containing GABAA (gamma-aminobutyric acid A) receptors. Accumulating clinical and preclinical evidence supports the antidepressant effects of exogenous administration of allopregnanolone analogs; yet, the role of endogenous allopregnanolone in the pathophysiology of depression remains unknown. METHODS: We utilized a chronic unpredictable stress (CUS) mouse model, followed by behavioral and biochemical assays, to examine whether altered neurosteroid signaling contributes to behavioral outcomes following CUS. We subsequently performed in vivo CRISPR (clustered regularly interspaced short palindromic repeats) knockdown of rate-limiting enzymes involved in allopregnanolone synthesis, 5α-reductase type 1 and 2 (5α1/2), in addition to lentiviral overexpression of 5α1/2 in the basolateral amygdala (BLA) of mice that underwent CUS to assess the impact of 5α1/2 on behavioral outcomes. RESULTS: The expression of δ subunit-containing GABAA receptors and endogenous levels of allopregnanolone were reduced in the BLA following CUS. Treatment with an exogenous allopregnanolone analog, SGE-516, was sufficient to increase allopregnanolone levels in the BLA following CUS. Knockdown of 5α1/2 in the BLA mimicked the behavioral outcomes associated with CUS. Conversely, overexpression of 5α1/2 in the BLA improved behavioral outcomes following CUS. CONCLUSIONS: Our findings demonstrate that chronic stress impairs endogenous neurosteroid signaling in the BLA, which is sufficient to induce behavioral deficits. Further, these studies suggest that allopregnanolone-based treatments may directly target the underlying pathophysiology of mood disorders suggesting that targeting endogenous neurosteroidogenesis may offer a novel therapeutic strategy.
Assuntos
Neuroesteroides , Pregnanolona , Camundongos , Animais , Receptores de GABA-A/metabolismo , Transdução de Sinais , Ácido gama-AminobutíricoRESUMO
Hyperpolarizing GABAAR currents, the unitary events that underlie synaptic inhibition, are dependent upon efficient Cl- extrusion, a process that is facilitated by the neuronal specific K+/Cl- co-transporter KCC2. Its activity is also a determinant of the anticonvulsant efficacy of the canonical GABAAR-positive allosteric: benzodiazepines (BDZs). Compromised KCC2 activity is implicated in the pathophysiology of status epilepticus (SE), a medical emergency that rapidly becomes refractory to BDZ (BDZ-RSE). Here, we have identified small molecules that directly bind to and activate KCC2, which leads to reduced neuronal Cl- accumulation and excitability. KCC2 activation does not induce any overt effects on behavior but prevents the development of and terminates ongoing BDZ-RSE. In addition, KCC2 activation reduces neuronal cell death following BDZ-RSE. Collectively, these findings demonstrate that KCC2 activation is a promising strategy to terminate BDZ-resistant seizures and limit the associated neuronal injury.