Spatial Learning and Memory in HIV-1 Transgenic Rats

Abstract

HIV-1 infection of the central nervous system impairs neural, cognitive, and behavioral functioning in patients despite antiretroviral therapy. However, studying mechanisms underlying HIV-1-related neurological and cognitive dysfunction has been limited without an adequate animal model. A novel, noninfectious HIV-1 transgenic (HIV-1Tg) rat model was recently created that expresses an HIV-1 provirus with a deletion of functional gag and pol genes. This HIV-1Tg rat reportedly develops clinical manifestations of human HIV disease and thus appears to mimic the persistent infection that results from the presence of HIV viral proteins in the host. We evaluated the HIV-1Tg rat model using the Morris water maze, a popular paradigm for testing learning and memory deficits in rodents. Because of congenital cataracts in HIV-1Tg rats, however, the traditional use of visual navigational cues in this paradigm were precluded. We first designed a modified Morris water maze and demonstrated that neurologically intact rats can effectively learn the water maze in the absence of visual cues and in the presence of non-visual navigation cues. We then tested HIV-1Tg rats in this modified Morris water maze. These HIV-1Tg rats showed a deficit in learning how to swim to the location of the hidden platform but did not show a deficit in their memory of the general location of the hidden platform. These results suggest that the noninfectious HIV-1Tg rat can be a valid model for the behavioral studies of HIV-related neurological dysfunction.

The HIV-1 transgenic rat model of neuroHIV

“…Both cART patients and the HIV-1Tg rat experience age-related immune-response alterations (Reid, Sadowska et al 2001), T-cell abnormalities (Reid, Abdelwahab et al 2004), kidney failure (Ray, Liu et al 2003), changes in behavior, and neuropathology (Reid, Sadowska et al 2001). HIV-1Tg rats exhibit learning deficits even before they develop symptomatic signs of HIV infection (Vigorito, LaShomb et al 2007; LaShomb, Vigorito et al 2008), which is consistent with the cognitive impairment reported in HIV-1 patients receiving cART, and suggests that, despite the lack of viral replication, the persistent presence of HIV-1 viral proteins continues to affect brain and immune cells, causing neurological and immunological damage (Rao, Kim et al 2011). …”

“…In a standard running wheel, HIV-1Tg rats run as much, or more, than controls during daily 20 min sessions (Chang and Vigorito 2006) and do not differ from controls in swim speeds during a water maze task (Vigorito 2007; Lashomb 2009). This suggests that adult transgenic rats with the gag-pol deleted HIV-1 provirus exhibit good motor competence, consistent motivated behaviors, and no illness behavior that could confound assessments of learning and cognition.…”

“…The tests were conducted under dim red light, and non-visual cues were added (olfactory and tactile intra-maze cues and an auditory extra-maze cue) to encourage the use of non-visual landmark cues (an allocentric strategy) rather than an egocentric swim strategy that did not rely on any available cues. HIV-1Tg rats consistently exhibit a deficit in the acquisition of the water maze task, either when the start location is varied from day-to-day (Vigorito 2007; Vigorito 2013), or when the start location is not varied (Lashomb 2009). …”

Neurotoxic profiles of HIV, psychostimulant drugs of abuse, and their concerted effect on the brain: Current status of dopamine system vulnerability in NeuroAIDS

“…Since the development of this model, the use of HIV-1 transgenic rats that express one or more HIVproteins, including Tat and gp120, has been developed (Mazzucchelli et al, 2004;Ray et al, 2003;Reid et al, 2004;Yadav et al, 2006). However, published investigations of CNS function in rats expressing HIV-protein(s) are almost nonexistent (however, see Vigorito et al, 2007;Reid et al, 2001), and the extent to which Tat and/or gp120 is expressed in the brain is not known. Thus, this model is currently relegated to developmental stages, but may hold promise, especially if HIV-proteins may be easily induced.…”

NeuroHIV and Use of Addictive Substances

“…Both HAART patients and the HIV-1Tg rat experience agerelated immune response alterations (Reid et al, 2001), T-cell abnormalities (Reid et al, 2004), kidney failure (Ray et al, 2003), changes in behavior, and neuropathology (Reid et al, 2001). HIV-1Tg rats exhibit learning deficits even before they develop symptomatic signs of HIV infection (LaShomb, Vigorito, & Chang, 2008;Vigorito, LaShomb, & Chang, 2007), which is consistent with the cognitive impairment reported in HIV-1 patients receiving HAART and suggests that, despite the lack of viral replication, the persistent presence of HIV-1 viral proteins continues to affect brain and immune cells, causing neurological and immunological damage (Rao et al, 2011).…”