Neurodegeneration Within the Amygdala Is Differentially Induced by Opioid and HIV-1 Tat Exposure

Abstract

Opioid use disorder (OUD) is a critical problem that contributes to the spread of HIV and may intrinsically worsen neuroHIV. Despite the advent of combined antiretroviral therapies (cART), about half of persons infected with HIV (PWH) experience cognitive and emotional deficits that can be exacerbated by opioid abuse. HIV-1 Tat is expressed in the central nervous system (CNS) of PWH on cART and is thought to contribute to neuroHIV. The amygdala regulates emotion and memories associated with fear and stress and is important in addiction behavior. Notwithstanding its importance in emotional saliency, the effects of HIV and opioids in the amygdala are underexplored. To assess Tat- and morphine-induced neuropathology within the amygdala, male Tat transgenic mice were exposed to Tat for 8 weeks and administered saline and/or escalating doses of morphine twice daily (s.c.) during the last 2 weeks of Tat exposure. Eight weeks of Tat exposure decreased the acoustic startle response and the dendritic spine density in the basolateral amygdala, but not the central nucleus of the amygdala. In contrast, repeated exposure to morphine alone, but not Tat, increased the acoustic startle response and whole amygdalar levels of amyloid-β (Aβ) monomers and oligomers and tau phosphorylation at Ser396, but not neurofilament light chain levels. Co-exposure to Tat and morphine decreased habituation and prepulse inhibition to the acoustic startle response and potentiated the morphine-induced increase in Aβ monomers. Together, our findings indicate that sustained Tat and morphine exposure differentially promote synaptodendritic degeneration within the amygdala and alter sensorimotor processing.

Effects of acute Δ9 -tetrahydrocannabinol on behavior and the endocannabinoid system in HIV-1 Tat transgenic female and male mice

“…Interestingly, in the presence of Tat the displayed anxiogenic effects of acute THC disappeared, which stays in contrast to the nding of higher e cacy of acute THC on nociception with Tat induction. The decrease of dendritic spine density in the amygdala upon Tat induction reported by a recent study(Nass et al, 2022) might contribute to the disruption of THC's effect on anxiety-like behavior, and thus maybe CNS-dependent.Additionally, whereas acute THC did not downregulate locomotor activity at any of the given doses, exploration behavior assessed in the novel object recognition task demonstrated decreased exploration of the presented objects for Tat(−) mice in the presence of THC, but not for Tat(+) mice. Thus, potential decreased exploratory movements around the elevated plus maze might have resulted in less pokes into the open arms and higher apparent anxiety for Tat(−) compared to Tat(+) mice.…”

Casein Kinase 2 Mediates HIV- and Opioid-Induced Pathologic Phosphorylation of TAR DNA Binding Protein 43 in the Basal Ganglia

“…Cytoplasmic TDP-43 inclusions promote the formation of pathologic tau aggregates, interact with tau to enhance the deposition of insoluble complexes, and worsen neurodegenerative outcomes (Latimer & Liachko, 2021; Latimer et al, 2022; Montalbano et al, 2020). We recently reported the presence of pathologic tau aggregates in striatal, amygdalar, and cerebral cortical brain regions with prolonged exposure to Tat and/or morphine (Kadri et al, 2015; Ohene-Nyako et al, 2021; Nass et al, 2022). Thus, the current findings provide a possible mechanism of HIV/HIV-1 Tat and opioid-induced neuronal injury via potential interactions between cytoplasmic pTDP-43 and pathologic tau aggregates.…”

“…every second day (until 40 mg/kg/day b.i.d. was achieved on day 7 and continued thereafter) during the last 2 weeks of Tat induction (Nass et al, 2021(Nass et al, , 2022Ohene-Nyako et al, 2021). Control mice received an equivalent volume of saline.…”

A new perspective on HIV: effects of HIV on brain-heart axis

“…Glu secreted by the CeA increases heart rate and blood pressure by activating the sympathetic nervous system, while GABA secreted by the CeA reduces heart rate and blood pressure by activating the parasympathetic nervous system (179)(180)(181). In HIV-infected individuals, degeneration or volume loss in the amygdala may impair the transmission of cardiovascular regulatory signals to areas such as the brainstem and hypothalamus, leading to changes in blood pressure and heart rate (182,183).…”