Sex-specific threat responding and neuronal engagement in carbon dioxide associated fear and extinction: Noradrenergic involvement in female mice.

Difficulty in appropriately responding to threats is a key feature of psychiatric disorders, especially fear-related conditions such as panic disorder (PD) and posttraumatic stress disorder (PTSD). Most prior work on threat and fear regulation involves exposure to external threatful cues. However, fear can also be triggered by aversive, within-the-body, sensations.

The subfornical organ regulates acidosis-evoked fear by engaging microglial acid-sensor TDAG8 and forebrain neurocircuits in male mice.

An important role of pH homeostasis has been suggested in the physiology of panic disorder, with acidosis as an interoceptive trigger leading to fear and panic. Identification of novel mechanisms that can translate acidosis into fear will promote a better understanding of panic physiology. The current study explores a role of the subfornical organ (SFO), a blood-brain barrier compromised brain area, in translating acidosis to fear-relevant behaviors.

Subfornical organ interleukin 1 receptor: A novel regulator of spontaneous and conditioned fear associated behaviors in mice.

Impaired threat responding and fear regulation is a hallmark of psychiatric conditions such as post-traumatic stress disorder (PTSD) and Panic Disorder (PD). Most studies have focused on external psychogenic threats to study fear, however, accumulating evidence suggests a primary role of homeostatic perturbations and interoception in regulating emotional behaviors. Heightened reactivity to interoceptive threat carbon dioxide (CO) inhalation associates with increased risk for developing PD and PTSD, however, contributory mechanisms and molecular targets are not well understood.

Immunomodulatory T cell death associated gene-8 (TDAG8) receptor in depression-associated behaviors.

Converging evidence supports neuroimmune factors in depression psychopathology. We previously reported reduced depression-like behavior in immunomodulatory G-protein-coupled receptor, T cell death-associated gene-8 (TDAG8) deficient mice. Here, we expand on those findings by investigating depression- and anxiety-associated behaviors, and cytokine profiles in TDAG8-deficient mice.

Recruitment of central angiotensin II type 1 receptor associated neurocircuits in carbon dioxide associated fear.

Individuals with fear-associated conditions such as panic disorder (PD) and posttraumatic stress disorder (PTSD) display increased emotional responses to interoceptive triggers, such as CO inhalation, that signal a threat to physiological homeostasis. Currently, effector systems and mechanisms underlying homeostatic modulation of fear memory are not well understood. In this regard, the renin angiotensin system (RAS), particularly the angiotensin receptor type 1 (AT1R), a primary homeostatic regulatory target, has gained attention.

Enhanced fear and altered neuronal activation in forebrain limbic regions of CX3CR1-deficient mice.

Mounting evidence supports immune dysfunction in psychiatric conditions such as post-traumatic stress disorder (PTSD). The association of immunomodulatory mechanisms with PTSD-relevant behavior and physiology is not well understood. Communication between neurons and microglia, resident immune cells of the central nervous system, is crucial for optimal regulation of behavior and physiology.

Differential behavioral sensitivity to carbon dioxide (CO) inhalation in rats.

Inhalation of carbon dioxide (CO) is frequently employed as a biological challenge to evoke intense fear and anxiety. In individuals with panic disorder, CO reliably evokes panic attacks. Sensitivity to CO is highly heterogeneous among individuals, and although a genetic component is implicated, underlying mechanisms are not clear.

Microglial Acid Sensing Regulates Carbon Dioxide-Evoked Fear.

Background: Carbon dioxide (CO2) inhalation, a biological challenge and pathologic marker in panic disorder, evokes intense fear and panic attacks in susceptible individuals. The molecular identity and anatomic location of CO2-sensing systems that translate CO2-evoked fear remain unclear. We investigated contributions of microglial acid sensor T cell death-associated gene-8 (TDAG8) and microglial proinflammatory responses in CO2-evoked behavioral and physiological responses.

Maternal immune activation alters glutamic acid decarboxylase-67 expression in the brains of adult rat offspring.

Activation of the maternal innate immune system, termed "maternal immune activation" (MIA), represents a common environmental risk factor for schizophrenia. Whereas evidence suggests dysregulation of GABA systems may underlie the pathophysiology of schizophrenia, a role for MIA in alteration of GABAergic systems is less clear. Here, pregnant rats received either the viral mimetic polyriboinosinic-polyribocytidilic acid or vehicle injection on gestational day 14.

Neuropeptide Y Impairs Retrieval of Extinguished Fear and Modulates Excitability of Neurons in the Infralimbic Prefrontal Cortex.

Unlabelled: Neuropeptide Y (NPY), a 36 aa peptide, regulates stress and emotional behaviors. Preclinical and clinical studies support an association of NPY with trauma-evoked syndromes such as posttraumatic stress disorder (PTSD), although the exact contribution of NPY is not clear. In the current study, we examined functional attributes of NPY in the infralimbic (IL) cortex, an area that regulates fear memories and is reported to be hypoactive in PTSD.

Modulation of schizophrenia-related genes in the forebrain of adolescent and adult rats exposed to maternal immune activation.

Maternal immune activation (MIA) is an environmental risk factor for schizophrenia, and may contribute to other developmental disorders including autism and epilepsy. Activation of pro-inflammatory cytokine systems by injection of the synthetic double-stranded RNA polyriboinosinic-polyribocytidilic acid (Poly I:C) mediates important neurochemical and behavioral corollaries of MIA, which have relevance to deficits observed in schizophrenia. We examined the consequences of MIA on forebrain expression of neuregulin-1 (NRG-1), brain-derived neurotrophic factor (BDNF) and their receptors, ErbB4 and trkB, respectively, genes associated with schizophrenia.

A potential role for the acid-sensing T cell death associated gene-8 (TDAG8) receptor in depression-like behavior.

Inflammation has been suggested to contribute to the pathophysiology of depression. The T cell death associated gene-8 (TDAG8) receptor is a proton-sensing G-protein-coupled receptor (GPCR) expressed on immune cells in both the CNS and periphery. Previous work has shown modulation of inflammation by the TDAG8 receptor, with pro-inflammatory responses reported in the central nervous system (CNS).

Evidence for involvement of nitric oxide and GABA(B) receptors in MK-801- stimulated release of glutamate in rat prefrontal cortex.

Systemic administration of NMDA receptor antagonists elevates extracellular glutamate within prefrontal cortex. The cognitive and behavioral effects of NMDA receptor blockade have direct relevance to symptoms of schizophrenia, and recent studies demonstrate an important role for nitric oxide and GABA(B) receptors in mediating the effects of NMDA receptor blockade on these behaviors. We sought to extend those observations by directly measuring the effects of nitric oxide and GABA(B) receptor mechanisms on MK-801-induced glutamate release in the prefrontal cortex.

Fluoxetine and aripiprazole treatment following prenatal immune activation exert longstanding effects on rat locomotor response.

Aim: Studies characterizing treatment interventions in a naturalistic setting suggest that antidepressant and antipsychotic medications may be equally effective in improving clinical outcome in individuals at high risk for first-episode psychosis. Of interest, both beneficial as well as potentially adverse effects have been observed following fluoxetine treatment in a mouse prenatal immune activation model of relevance to psychosis prevention. We sought to extend those findings by examining the effects of fluoxetine, as well as the antipsychotic medication aripiprazole, in a rat prenatal immune activation model.

Effects of prenatal immune activation and peri-adolescent stress on amphetamine-induced conditioned place preference in the rat.

Rationale: Addiction is a disease of learning and memory, as learning processes underlying acquisition, extinction, and reinstatement of drug-paired associations play central roles in addiction. Early developmental stress enhances risk for drug problems in adulthood. Environmental factors influencing learning and memory processes relevant to addiction remain incompletely characterized.

Effect of paliperidone and risperidone on extracellular glutamate in the prefrontal cortex of rats exposed to prenatal immune activation or MK-801.

The NMDA glutamate hypofunction model of schizophrenia is based in part upon acute effects of NMDA receptor blockade in humans and rodents. Several laboratories have reported glutamate system abnormalities following prenatal exposure to immune challenge, a known environmental risk factor for schizophrenia. Here we report indices of NMDA glutamate receptor hypofunction following prenatal immune activation, as well as the effects of treatment during periadolescence with the atypical antipsychotic medications risperidone and paliperidone.

Effects of risperidone and paliperidone pre-treatment on locomotor response following prenatal immune activation.

Aim: Limited data are available regarding pharmacological characteristics of effective interventions for psychosis prevention. Enrollment challenges in psychosis prevention trials impede screening diverse interventions for efficacy. Relevant animal models could help circumvent this barrier.

Individual differences in maternal response to immune challenge predict offspring behavior: contribution of environmental factors.

Maternal infection during pregnancy elevates risk for schizophrenia and related disorders in offspring. Converging evidence suggests the maternal inflammatory response mediates the interaction between maternal infection, altered brain development, and behavioral outcome. The extent to which individual differences in the maternal response to immune challenge influence the development of these abnormalities is unknown.

Dopaminergic regulation of dopamine D3 and D3nf receptor mRNA expression.

Dopamine D3 receptors have the highest dopamine affinity of all dopamine receptors, and may thereby regulate dopamine signaling mediated by volume transmission. Changes in D3 receptor isoform expression may alter D3 receptor function, however, little is known regarding coordination of D3 isoform expression in response to perturbations in dopaminergic stimulation. To determine the effects of dopamine receptor stimulation and blockade on D3 receptor alternative splicing, we determined D3 and D3nf isoform mRNA expression following treatment with the D3 receptor antagonist NGB 2904, and the indirect dopamine agonist amphetamine.

Relative expression of D3 dopamine receptor and alternative splice variant D3nf mRNA in high and low responders to novelty.

Studies in rodents suggest an important role for the D3 dopamine receptor in regulating locomotor responses to spatial novelty and psychostimulants. The D3 receptor alternatively spliced variant D3nf produces a non-dopamine binding protein that may alter D3 receptor localization by dimerizing with the full-length receptor. In the high responder/low responder (HR/LR) model, the locomotor response to an inescapable, novel spatial environment predicts individual differences in the locomotor and rewarding effects of psychostimulants.

Risperidone pretreatment prevents elevated locomotor activity following neonatal hippocampal lesions.

Long-standing behavioral abnormalities emerge after puberty in rats following neonatal hippocampal lesion, providing a developmental model of abnormal rat behavior that may have predictive validity in identifying compounds effective in treating symptoms of schizophrenia. We sought to test the predictive validity of the neonatal hippocampal lesion model in identifying preventive treatment for first-episode psychosis. We determined the effect of risperidone, recently studied for prevention of first-episode psychosis, on the development of elevated locomotor activity following neonatal hippocampal lesions.