ABSTRACT
HIV-1-associated neurocognitive disorders (HAND) are a major comorbidity of HIV-1 infection, marked by impairment of executive function varying in severity. HAND affects nearly half of people living with HIV (PLWH), with mild forms predominating since the use of anti-retroviral therapies (ART). The HIV-1 transactivator of transcription (Tat) protein is found in the cerebrospinal fluid of patients adherent to ART, and its administration or expression in animals causes cognitive symptoms. Studies of Tat interaction with the N-methyl-D-aspartate receptor (NMDAR) suggest that glutamate toxicity contributes to Tat-induced impairments. To identify changes in regional glutamatergic circuitry underlying cognitive impairment, we injected recombinant Tat86 or saline to medial prefrontal cortex (mPFC) of male Sprague-Dawley rats. Rats were assessed with behavioral tasks that involve intact functioning of mPFC including the novel object recognition (NOR), spatial object recognition (SOR), and temporal order (TO) tasks at 1 and 2 postoperative weeks. Following testing, mPFC tissue was collected and analyzed by RT-PCR. Results showed Tat86 in mPFC-induced impairment in SOR, and upregulation of Grin1 and Grin2a transcripts. To further understand the mechanism of Tat toxicity, we assessed the effects of full-length Tat101 on gene expression in mPFC by RNA sequencing. The results of RNAseq suggest that glutamatergic effects of Tat86 are maintained with Tat101, as Grin2a was upregulated in Tat101-injected tissue, among other differentially expressed genes. Spatial learning and memory impairment and Grin2a upregulation suggest that exposure to Tat protein drives adaptation in mPFC, altering the function of circuitry supporting spatial learning and memory.
ABSTRACT
The locus coeruleus (LC) is a critical node in the stress response, and its activation has been shown to promote hypervigilance and anxiety-like behavior. This noradrenergic nucleus has historically been considered homogeneous with highly divergent neurons that operate en masse to collectively affect central nervous system function and behavioral state. However, in recent years, LC has been identified as a heterogeneous structure whose neurons innervate discrete terminal fields and contribute to distinct aspects of behavior. We have previously shown that in late adolescent male rats, an acute traumatic stressor, simultaneous physical restraint and exposure to predator odor, preferentially induces c-Fos expression in a subset of dorsal LC neurons and persistently increases anxiety-like behavior. To investigate how these neurons respond to and contribute to the behavioral response to stress, we used a combination of retrograde tracing, whole-cell patch clamp electrophysiology, and chemogenetics. Here we show that LC neurons innervating the central nucleus of the amygdala (CeA) and medial prefrontal cortex (mPFC) undergo distinct electrophysiological changes in response to stressor exposure and have opposing roles in mediating anxiety-like behavior. While neurons innervating CeA become more excitable in response to stress and promote anxiety-like behavior, those innervating mPFC become less excitable and appear to promote exploration. These findings show that LC neurons innervating distinct terminal fields have unique physiological responses to particular stimuli. Furthermore, these observations advance the understanding of the LC as a complex and heterogeneous structure whose neurons maintain unique roles in various forms of behavior.
