Both HIV and Tat expression decrease prepulse inhibition with further impairment by methamphetamine

Abstract

HIV infection and methamphetamine (METH) use are highly comorbid and represent a significant public health problem. Both conditions are known to negatively impact a variety of brain functions. One brain function that may be affected by HIV and METH use is sensorimotor gating, an automatic, pre-conscious filtering of sensory information that is thought to contribute to higher order cognitive processes. Sensorimotor gating is often measured using prepulse inhibition (PPI), a paradigm that can be conducted in both humans and animals, thereby enabling crossspecies translational studies. While previous studies suggest HIV and METH may individually impair PPI, little research has been conducted on the effects of combined HIV and METH on PPI.The goal of this cross-species study was to determine the effects of METH on PPI in the inducible Tat (iTat) mouse model of HIV and in people with HIV. PPI was measured in the iTat mouse model before, during, and after chronic METH treatment and after Tat induction. Chronic METH treatment decreased PPI in male but not female mice. PPI normalized with cessation of METH.Inducing Tat expression decreased PPI in male but not in female mice. No interactions between chronic METH treatment and Tat expression were observed in mice. In humans, HIV was associated with decreased PPI in both men and women. Furthermore, PPI was lowest in people with HIV who also had a history of METH dependence. Overall, these results suggest HIV and METH may additively impair early information processing in humans, potentially affecting downstream cognitive function.

HIV Transgenic Rats Demonstrate Impaired Sensorimotor Gating But Are Insensitive to Cannabinoid (Δ9-Tetrahydrocannabinol)-Induced Deficits

“…Consistent with our primary hypothesis and with findings in PWH ( Minassian et al, 2013 ; Walter et al, 2021 ), HIVtg rats exhibited PPI deficits relative to WT controls. Our secondary hypothesis was also supported, as an altered sensitivity to THC was observed in HIVtg vs WT rats.…”

“…To wit, the present paradigm manipulated prepulse intensity, while previous studies manipulated inter-stimulus interval (ISI; e.g., Moran et al, 2012 ). While our decision to eschew ISI manipulation precluded investigation of the robust timing deficits of the HIVtg rat ( McLaurin et al, 2019a ), the present paradigm was chosen because it was deemed more likely to recreate the specific PPI deficit observed in HAND patients ( Walter et al, 2021 ; Minassian et al, 2013 ). This judgment was made for 2 reasons.…”

“…Also subserved by fronto-striatal circuitry is sensorimotor gating, the pre-attentive process mediating the suppression of motor responses to irrelevant sensory stimuli ( Swerdlow et al, 2001 ). Prepulse inhibition (PPI), the attenuation of the startle response to a sudden high-intensity stimulus by the perception of a preceding non-startling stimulus ( Figure 1 ), is an operational measure of sensorimotor gating that is deficient in a range of neurological disorders, including HIV/HAND ( Minassian et al, 2013 , Walter et al, 2021 ). While certainly not a proxy for cognition per se, PPI can be used to probe the integrity of descending forebrain circuitry that may be implicated in psychopathology-related cognitive dysfunction ( Swerdlow et al, 2016 ).…”

“…Studies of sensorimotor gating in PWH provide evidence for such a correlation in the HIV disease state. One of 2 such studies of which we are aware identified PPI deficits in only those PWH meeting criteria for HAND ( Minassian et al, 2013 ), while the second revealed significant correlations between PPI and learning, memory, motor function, and global deficit scores in a much larger cohort of HIV + males (although the specificity of PPI deficits to HAND was not replicated) ( Walter et al, 2021 ). While these correlations by no means guarantee shared etiology between these 2 classes of deficits (disruptions of any one or combination of nuclei within the startle circuit may decrease PPI; Swerdlow et al, 2008 ), they may indicate some degree of overlap between the circuit-level pathology underlying HIV-mediated PPI deficiency and that effecting the pattern of neurocognitive impairment specific to HAND.…”

Synergistic Impairment of the Neurovascular Unit by HIV-1 Infection and Methamphetamine Use: Implications for HIV-1-Associated Neurocognitive Disorders

“…While METH use has been found to be associated with sustained attention and vigilance deficits in humans, no interaction between HIV-1 and METH effects were found in a recent study [ 137 ]. Furthermore, prepulse inhibition (PPI) of the acoustic startle response, a measure of sensorimotor gating, has been reported to be the lowest in people with HIV-1 who also had a history of METH dependence [ 138 ]. These observations suggest that HIV-1 and METH may additively impair early information processing, potentially affecting downstream cognitive function.…”