Landhing M. Moran

Neurobehavioral alterations in HIV-1 transgenic rats: Evidence for dopaminergic dysfunction

Clinical studies have provided evidence that the progression of HIV-1-associated neurocognitive disorders (HAND) involves alterations in dopamine (DA) systems. Drugs of abuse that act on the brain DA system, such as cocaine (Coc), may exacerbate HIV-1 infection and consequent behavioral and neurological manifestations. In the present study, we used the HIV-1 transgenic (Tg) rat, which constitutively expresses 7 of the 9 HIV-1 genes, to assess potential DA system alterations in three behavioral assays: prepulse inhibition (PPI) of the auditory startle response (ASR), novelty and habituation/retention, and sensitization to Coc across repeated administration. Adult female Sprague-Dawley rats were tested in each experiment. The HIV-1 Tg animals were hyperreactive to auditory startle stimuli and displayed a leftward shift in the temporal window for maximal PPI, suggesting an alteration in sensorimotor gating. All animals displayed an initial robust locomotor response to a novel environment which dissipated with repeated testing; however, the HIV-1 Tg rats, relative to controls, consistently showed a weaker novelty response across monthly-spaced assessments. The HIV-1 Tg animals also showed decreased intrasession habituation of motor activity across 3-day periods that emerged across monthly-spaced locomotor activity sessions; a pattern consistent with impaired long-term episodic memory. Furthermore, the HIV-1 Tg group displayed differential cocaine-induced sensitization, observed both in initiation across the 10-day cocaine treatment, and in expression following a cocaine rechallenge after a 7-day abstinence. Collectively, the present data implicate that the non-infectious HIV-1 Tg rat, which resembles the complete suppression of infection in HIV-1 positive individuals under CART, displays sustained, if not permanent, alterations in the brain DA system.

Neonatal intrahippocampal HIV-1 protein Tat1-86 injection: Neurobehavioral alterations in the absence of increased inflammatory cytokine activation

Pediatric AIDS caused by human immunodeficiency virus type 1 (HIV‐1) remains one of the leading worldwide causes of childhood morbidity and mortality. HIV‐1 proteins, such as Tat and gp120, are believed to play a crucial role in the neurotoxicity of pediatric HIV‐1 infection. Detrimental effects on development, behavior, and neuroanatomy follow neonatal exposure to the HIV‐1 viral toxins Tat1–72 and gp120. The present study investigated the neurobehavioral effects induced by the HIV‐1 neurotoxic protein Tat1–86, which encodes the first and second exons of the Tat protein. In addition, the potential effects of HIV‐1 toxic proteins Tat1–86 and gp120 on inflammatory pathways were examined in neonatal brains. Vehicle, 25 μg Tat1–86 or 100 ng gp120 was injected into the hippocampus of male Sprague–Dawley pups on postnatal day 1 (PD1). Tat1–86 induced developmental neurotoxic effects, as witnessed by delays in eye opening, delays in early reflex development and alterations in prepulse inhibition (PPI) and between‐session habituation of locomotor activity. Overall, the neurotoxic profile of Tat1–86 appeared more profound in the developing nervous system in vivo relative to that seen with the first exon encoded Tat1–72 (Fitting et al., 2008b), as noted on measures of eye opening, righting reflex, and PPI. Neither the direct PD1 CNS injection of the viral HIV‐1 protein variant Tat1–86, nor the HIV‐1 envelope protein gp120, at doses sufficient to induce neurotoxicity, necessarily induced significant expression of the inflammatory cytokine IL‐1β or inflammatory factors NF‐κβ and I‐κβ. The findings agree well with clinical observations that indicate delays in developmental milestones of pediatric HIV‐1 patients, and suggest that activation of inflammatory pathways is not an obligatory response to viral protein‐induced neurotoxicity that is detectable with behavioral assessments. Moreover, the amino acids encoded by the second tat exon may have unique actions on the developing hippocampus.

The role of sensory modality in prepulse inhibition: An ontogenetic study

Deficits in prepulse inhibition (PPI), a measure of sensorimotor gating, are observed in neurodevelopmental and neuropsychiatric disorders. Despite the large PPI literature, the majority of studies characteristically employ tests with one interstimulus interval (ISI), of one modality, at one age. In the context of the auditory startle response (ASR), the present study examined (1) the profile for the ontogeny of PPI through adulthood in Long-Evans hooded rats with a reasonably comprehensive ISI function, (2) whether the ontogenetic profile for PPI is sensitive to modality of the prepulse stimulus, as a within-session variable, and (3) whether the maturation of PPI differs for males and females. Despite the basic effect of more pronounced PPI in adult relative to preweanling animals, each sensory modality displayed a unique ontogenetic profile for PPI, without any compelling evidence for major differences between males and females, in accordance with the known temporal course of peripheral and central maturational profiles of sensory systems in the rat. The context for assessing auditory PPI (auditory and tactile vs. auditory and visual prepulses) influenced the overall startle response, i.e., a shift in the height of the entire profile, but did not significantly impact the auditory PPI profile per se. The translational relevance of preclinical sensorimotor assessments to patients with neurodevelopmental and/or neuropsychiatric disorders depends partly on an understanding of the ontogeny of sensorimotor gating in different sensory systems, and can be strengthened with the use of a reasonably comprehensive number of ISIs to provide relatively precise and defined response functions.

Prenatal IV Cocaine: Alterations in Auditory Information Processing

One clue regarding the basis of cocaine-induced deficits in attentional processing is provided by the clinical findings of changes in the infants’ startle response; observations buttressed by neurophysiological evidence of alterations in brainstem transmission time. Using the IV route of administration and doses that mimic the peak arterial levels of cocaine use in humans, the present study examined the effects of prenatal cocaine on auditory information processing via tests of the auditory startle response (ASR), habituation, and prepulse inhibition (PPI) in the offspring. Nulliparous Long–Evans female rats, implanted with an IV access port prior to breeding, were administered saline, 0.5, 1.0, or 3.0 mg/kg/injection of cocaine HCL (COC) from gestation day (GD) 8–20 (1×/day-GD8–14, 2×/day-GD15–20). COC had no significant effects on maternal/litter parameters or growth of the offspring. At 18–20 days of age, one male and one female, randomly selected from each litter displayed an increased ASR (>30% for males at 1.0 mg/kg and >30% for females at 3.0 mg/kg). When reassessed in adulthood (D90–100), a linear dose–response increase was noted on response amplitude. At both test ages, within-session habituation was retarded by prenatal cocaine treatment. Testing the females in diestrus vs. estrus did not alter the results. Prenatal cocaine altered the PPI response function across interstimulus interval and induced significant sex-dependent changes in response latency. Idazoxan, an α2-adrenergic receptor antagonist, significantly enhanced the ASR, but less enhancement was noted with increasing doses of prenatal cocaine. Thus, in utero exposure to cocaine, when delivered via a protocol designed to capture prominent features of recreational usage, causes persistent, if not permanent, alterations in auditory information processing, and suggests dysfunction of the central noradrenergic circuitry modulating, if not mediating, these responses.

HIV-1 proteins dysregulate motivational processes and dopamine circuitry

Motivational alterations, such as apathy, in HIV-1+ individuals are associated with decreased performance on tasks involving frontal-subcortical circuitry. We used the HIV-1 transgenic (Tg) rat to assess effect of long-term HIV-1 protein exposure on motivated behavior using sucrose (1–30%, w/v) and cocaine (0.01–1.0 mg/kg/infusion) maintained responding with fixed-ratio (FR) and progressive-ratio (PR) schedules of reinforcement. For sucrose-reinforced responding, HIV-1 Tg rats displayed no change in EC50 relative to controls, suggesting no change in sucrose reinforcement but had a downward shifted concentration-response curves, suggesting a decrease in response vigor. Cocaine-maintained responding was attenuated in HIV-1 Tg rats (FR1 0.33 mg/kg/infusion and PR 1.0 mg/kg/infusion). Dose-response tests (PR) revealed that HIV-1 Tg animals responded significantly less than F344 control rats and failed to earn significantly more infusions of cocaine as the unit dose increased. When choosing between cocaine and sucrose, control rats initially chose sucrose but with time shifted to a cocaine preference. In contrast, HIV-1 disrupted choice behaviors. DAT function was altered in the striatum of HIV-1 Tg rats; however, prior cocaine self-administration produced a unique effect on dopamine homeostasis in the HIV-1 Tg striatum. These findings of altered goal directed behaviors may determine neurobiological mechanisms of apathy in HIV-1+ patients.

Animal Models: Behavior and Pathology: Preclinical Assessment of the Putative Cognitive Deficits in HAND

Despite the reduced prevalence of HIV-1-associated dementia in the era of combination antiretroviral therapy (CART), nearly half of all HIV-1-positive individuals on CART are afflicted with mild to severe HIV-1-associated neurocognitive disorders (HAND). A greater understanding of the progression of HAND and the development of potential therapeutics require preclinical studies that utilize an integrative profile of cognitive function, from which valid inferences can be drawn about underlying processes. We propose a set of preclinical behavioral tasks that tap various components of executive function, the cognitive domain which shows the greatest decline in the progression of HAND. Fronto-striatal circuitry and dopaminergic systems are integral to executive function and are also particularly vulnerable to injury by HIV-1 infection. The tasks described in this chapter provide measures that are both sensitive to alterations in the function of these systems and relevant to typical cognitive deficits observed in HAND. Further, each of the tasks presently described has a very clear human analogue. Prepulse inhibition of the auditory startle response is a measure of preattentive processing and sensory gating. The multi-choice serial reaction time task assesses different types of attentional processes, including sustained attention, selective attention, and set-shifting. The Morris water maze provides a profile of reference and working memory. Within each behavioral measure, there are a number of variables, which can be manipulated to provide information on several components of executive function, affording the opportunity to model the specific cognitive deficits of HAND.