T cells clear virus from the CNS and dynamically regulate brain functions, including spatial learning, through cytokine signaling. Here we determined whether hippocampal T cells that persist after recovery from infection with West Nile virus (WNV) or Zika virus (ZIKV) impact hippocampal-dependent learning and memory. Using newly established models of viral encephalitis recovery in adult animals, we show that in mice that have recovered from WNV or ZIKV infection, T cell-derived interferon-γ (IFN-γ) signaling in microglia underlies spatial-learning defects via virus-target-specific mechanisms. Following recovery from WNV infection, mice showed presynaptic termini elimination with lack of repair, while for ZIKV, mice showed extensive neuronal apoptosis with loss of postsynaptic termini. Accordingly, animals deficient in CD8+ T cells or IFN-γ signaling in microglia demonstrated protection against synapse elimination following WNV infection and decreased neuronal apoptosis with synapse recovery following ZIKV infection. Thus, T cell signaling to microglia drives post-infectious cognitive sequelae that are associated with emerging neurotropic flaviviruses.

Memory impairment following West Nile virus neuroinvasive disease (WNND) is associated with loss of hippocampal synapses with lack of recovery. Adult neurogenesis and synaptogenesis are fundamental features of hippocampal repair, suggesting viruses impact these processes. Here, using an established model of WNND-induced cognitive dysfunction, transcriptional profiling revealed alterations in gene expression that limit adult neurogenesis, including interleukin (IL)-1. WNND-recovered animals exhibit decreased neuroblasts and increased astrogenesis, without recovery of hippocampal neurogenesis at thirty days. Analysis of cytokine production in ex vivo isolated microglia and astrocytes revealed the latter to be the predominant source of IL-1. IL-1R1-deficient, WNND-recovered mice exhibit normal neurogenesis, recovery of presynaptic termini, and resistance to spatial learning defects, the latter of which likewise occurred after treatment with IL-1R1 antagonist. Thus, preferential generation of proinflammatory astrocytes impairs neuronal progenitor cell homeostasis via expression of IL-1, which may underlie long-term cognitive consequences of WNND, but provides a therapeutic target.

Background Carbon dioxide (CO2) inhalation, a biological challenge and pathological marker in Panic Disorder, evokes intense fear and panic attacks in susceptible individuals. The molecular identity and anatomical location of CO2-sensing systems that translate CO2-evoked fear remains unclear. We investigated contributions of microglial acid sensor T cell death associated gene-8 (TDAG8) and microglial pro-inflammatory responses in CO2-evoked behavioral and physiological responses. Methods CO2-evoked freezing, autonomic and respiratory responses were assessed in TDAG8-deficient (−/−) and wildtype (+/+) mice. Involvement of TDAG8-dependent microglial activation and pro-inflammatory cytokine IL-1β with CO2-evoked responses was investigated using microglial blocker, minocycline and IL-1β antagonist, IL- 1RA. CO2-chemosensitive firing responses using single-cell patch clamping were measured in TDAG8−/− and +/+ mice to gain functional insights. Results; TDAG8 expression was localized in microglia enriched within the sensory circumventricular organs (CVOs). TDAG8−/− mice displayed attenuated CO2-evoked freezing and sympathetic responses. TDAG8 deficiency was associated with reduced microglial activation and pro-inflammatory cytokine, IL-1β within the subfornical organ (SFO). Central infusion of microglial activation blocker, minocycline and IL-1β antagonist, IL-1RA attenuated CO2-evoked freezing. Finally, CO2-evoked neuronal firing in patch clamped SFO neurons was dependent on acid sensor TDAG8 and IL-1β. Conclusions Our data identify TDAG8-dependent microglial acid-sensing as a unique chemosensor for detecting and translating hypercapnia to fear-associated behavioral and physiological responses, providing a novel mechanism for homeostatic threat detection of relevance to psychiatric conditions such as panic disorder.

and coverslips were applied with ProLong Gold Antifade Mountant (Thermo Fisher Scientific). Immunofluorescence was captured using a Zeiss LSM 510 laser-scanning confocal microscope. Statistics. Survival curve comparisons were performed using GraphPad Prism software, which uses the log-rank test. Values for viral burden, cytokine production, and antibody and T cell response experiments are presented as the mean ± SEM. P values for these experiments were calculated with an unpaired, 2-tailed Student's t test. Statistical significance was accepted at a P value of less than 0.05. Study approval. All experiments were performed in compliance with and under the approval of the IACUC of UTMB.

Panic disorder (PD), a complex anxiety disorder characterized by recurrent panic attacks, represents a poorly understood psychiatric condition which is associated with significant morbidity and an increased risk of suicide attempts and completed suicide. Recently however, neuroimaging and panic provocation challenge studies have provided insights into the pathoetiology of panic phenomena and have begun to elucidate potential neural mechanisms that may underlie panic attacks. In this regard, accumulating evidence suggests that acidosis may be a contributing factor in induction of panic. Challenge studies in patients with PD reveal that panic attacks may be reliably provoked by agents that lead to acid–base dysbalance such as CO2 inhalation and sodium lactate infusion. Chemosensory mechanisms that translate pH into panic-relevant fear, autonomic, and respiratory responses are therefore of high relevance to the understanding of panic pathophysiology. Herein, we provide a current update on clinical and preclinical studies supporting how acid–base imbalance and diverse chemosensory mechanisms may be associated with PD and discuss future implications of these findings.