Abstract
Nearly half of all HIV-1-positive individuals on combination antiretroviral therapy (cART) are afflicted with HIV-1-associated neurocognitive disorders (HAND). The most prevalent cognitive deficits observed in the cART era are those of attention and executive function. Presently, we sought to model deficits in attention and core components of executive function (inhibition, flexibility, and set-shifting) observed in HAND using the HIV-1 transgenic (Tg) rat, which expresses 7 of the 9 HIV-1 genes. Ovariectomized female Fischer HIV-1 Tg and non-transgenic control rats (ns = 39–43) were tested in a series of operant tasks: signal detection, discrimination learning, reversal learning, and extradimensional set-shifting. The HIV-1 Tg animals attained the criterion of three sessions at 70 % accuracy at a significantly slower rate than the control animals on all tasks with the exception of the extradimensional set-shifting task. Of the animals that met the criteria, there was no significant difference in percent accuracy in any task. However, the HIV-1 Tg rats showed a lower overall response rate in signal detection and discrimination learning. A discriminant function analysis classified the animals by genotype with 90.4 % accuracy based on select measures of their performance. The functional consequences of chronic low-level expression of the HIV-1 proteins on attention, as well as inhibition and flexibility as core components of executive function, are apparent under conditions which resemble the brain proinflammatory immune responses and suppression of infection in HIV-1+ individuals under cART. Deficits in attention and core components of executive function may reflect an underlying impairment in temporal processing in HAND.
Similar content being viewed by others
References
Aksenov MY, Aksenova MV, Silvers JM, Mactutus CF, Booze RM (2008) Different effects of selective dopamine uptake inhibitors, GBR 12909 and WIN 35428, on HIV-1 Tat toxicity in rat fetal midbrain neurons. Neurotoxicology 29:971–977
Aksenova MV, Silvers JM, Aksenov MY, Nath A, Ray PD, Mactutus CF, Booze RM (2006) HIV-1 Tat neurotoxicity in primary cultures of rat midbrain fetal neurons: changes in dopamine transporter binding and immunoreactivity. Neurosci Lett 395:235–239
Ances BM, Ellis RJ (2007) Dementia and neurocognitive disorders due to HIV-1 infection. Semin Neurol 27:86–92
Antinori A, Arendt G, Becker JT, Brew BJ, Byrd DA, Cherner M, Clifford DB et al (2007) Updated research nosology for HIV-associated neurocognitive disorders. Neurology 69:1789–1799
Aston-Jones G, Cohen JD (2005) An integrative theory of locus coeruleus-norepinephrine function: adaptive gain and optimal performance. Annu Rev Neurosci 28:403–450
Bari A, Eagle DM, Mar AC, Robinson ES, Robbins TW (2009) Dissociable effects of noradrenaline, dopamine, and serotonin uptake blockade on stop task performance in rats. Psychopharmacology 205:273–283
Basso MR, Bornstein RA (2003) Effects of past noninjection drug abuse upon executive function and working memory in HIV infection. J Clin Exp Neuropsychol 25:893–903
Berger JR, Nath A (1997) HIV dementia and the basal ganglia. Intervirology 40:122–131
Berger JR, Kumar M, Kumar A, Fernandez JB, Levin B (1994) Cerebrospinal fluid dopamine in HIV-1 infection. AIDS 8:67–71
Birrell JM, Brown VJ (2000) Medial frontal cortex mediates perceptual attentional set shifting in the rat. J Neurosci 20:4320–4324
Bushnell PJ (1998) Behavioral approaches to the assessment of attention in animals. Psychopharmacology 138:231–259
Carli M, Robbins TW, Evenden JL, Everitt BJ (1983) Effects of lesions to ascending noradenergic neurones on performance of a 5-choice serial reaction task in rats; implications for theories of dorsal noradenergic bundle function based on selective attention and arousal. Behav Brain Res 9:361–380
Cattie JE, Doyle K, Weber E, Grant I, Woods SP (2012) Planning deficits in HIV-associated neurocognitive disorders: component processes, cognitive correlates, and implications for everyday functioning. J Clin Exp Neuropsychol 34:906–918
Centers for Disease Control and Prevention (2012) New HIV infections in the United States. http://www.cdc.gov/nchhstp/newsroom/docs/2012/HIV-Infections-2007–2010.pdf
Chang L, Speck O, Miller EN, Braun J, Jovicich J, Koch C, Itti L, Ernst T (2001) Neural correlates of attention and working memory deficits in HIV patients. Neurology 57:1001–1007
Chang L, Ernst T, Witt MD, Ames N, Gaiefsky M, Miller E (2002) Relationships among brain metabolites, cognitive function, and viral loads in antiretroviral-naïve HIV patients. J Neuroimaging 17:1638–1648
Chang L, Wang GJ, Volkow ND, Ernst T, Telang F, Logan J, Fowler JS (2008) Decreased brain dopamine transporters are related to cognitive deficits in HIV patients with or without cocaine abuse. J Neuroimaging 42:869–878
Chudasama Y, Robbins TW (2004) Dopaminergic modulation of visual attention and working memory in the rodent prefrontal cortex. Neuropsychopharmacology 29:1628–1636
Clarke HF, Hill GJ, Robbins TW, Roberts AC (2011) Dopamine, but not serotonin, regulates reversal learning in the marmoset caudate nucleus. J Neurosci 16:4290–4297
Clatworthy PL, Lewis SJ, Brichard L, Hong YT, Izquierdo D, Clark L et al (2009) Dopamine release in dissociable striatal subregions predicts the different effects of oral methylphenidate on reversal learning and spatial working memory. J Neurosci 29:4690–4696
Crofts HS, Dalley JW, Collins P, Van Denderen JC, Everitt BJ, Robbins TW et al (2001) Differential effects of 6-OHDA lesions of the frontal cortex and caudate nucleus on the ability to acquire an attentional set. Cereb Cortex 11:1015–1026
Cysique LA, Maruff P, Brew BJ (2004) Prevalence and pattern of neuropsychological impairment in human immunodeficiency virus-infected/acquired immunodeficiency syndrome (HIV/AIDS) patients across pre- and post-highly active antiretroviral therapy eras: a combined study of two cohorts. J Neurovirol 10:350–357
di Rocco A, Bottiglieri T, Dorfman D, Werner P, Morrison C, Simpson D (2000) Decreased homovanillic acid in cerebrospinal fluid correlates with impaired neuropsychologic function in HIV-1-infected patients. Clin Neuropharmacol 23:190–194
Dias R, Robbins TW, Roberts AC (1996) Primate analogue of the Wisconsin card sorting test: effects of excitotoxic lesions of the prefrontal cortex in the marmoset. Behav Neurosci 110:872–886
Ernst T, Chang L, Jovicich J, Ames N, Arnold S (2002) Abnormal brain activation on functional MRI in cognitively asymptomatic HIV patients. Neurology 59:1343–1349
Everall IP, Heaton RK, Marcotte TD, Ellis RJ, McCutchan JA, Atkinson JH, Grant I, Mallory M, Masliah E (1999) Cortical synaptic density is reduced in mild to moderate human immunodeficiency virus neurocognitive disorder. Brain Pathol 9:209–217
Fein G, Biggins CA, Mackay S (1995) Delayed latency of the event-related brain potential P3A component in HIV disease. Progressive effects with increasing cognitive impairment. Arch Neurol 52:1109–1118
Ferris MJ, Frederick-Duus D, Fadel J, Mactutus CF, Booze RM (2009) The human immunodeficiency virus-1-associated protein, Tat(1–86), impairs dopamine transporters and interacts with cocaine to reduce nerve terminal function: a no-net-flux microdialysis study. Neuroscience 159:1292–1299
Garvey LJ, Yerrakalva D, Winston A (2009) Correlations between computerized battery testing and a memory questionnaire for identification of neurocognitive impairment in HIV type 1-infected subjects on stable antiretroviral therapy. AIDS Res Hum Retrovir 25:765–769
Granon S, Passetti F, Thomas KL, Dalley JW, Everitt BJ, Robbins TW (2000) Enhanced and impaired attentional performance after infusion of D1 dopaminergic receptor agents into rat prefrontal cortex. J Neurosci 20:1208–1215
Groman SM, Lee B, London ED, Mandelkern MA, James AS, Feiler K et al (2011) Dorsal striatal D2-like receptor availability covaries with sensitivity to positive reinforcement during discrimination learning. J Neurosci 31:7291–7299
Hardy DJ, Hinkin CH (2002) Reaction time performance in adults with HIV/AIDS. J Clin Exp Neuropsychol 24:912–929
Heaton RK, Clifford DB, Franklin DR, Woods SP, Ake C, Vaida F, Ellis RJ et al (2010) HIV-associated neurocognitive disorders persist in the era of potent antiretroviral therapy CHARTER study. Neurology 75:2087–2096
Heaton RK, Franklin DR, Ellis RJ, McCutchan JA, Letendre SL, LeBlanc S, Corkran SH et al (2011) HIV-associated neurocognitive disorders before and during the era of combination antiretroviral therapy: differences in rates, nature, and predictors. J Neurovirol 17:3–16
Himmelheber A, Sarter M, Bruno J (2000) Increases in cortical acetylcholine release during sustained attention performance in rat. Cogn Brain Res 9:313–325
Iudicello JE, Woods SP, Weber E, Dawson MS, Scott JC, Carey CL, Grant I (2008) Cognitive mechanisms of switching in HIV-associated category fluency deficits. J Clin Exp Neuropsychol 30:797–804
Kellendonk C, Simpson EH, Polan HJ, Malleret G, Vronskaya S, Winiger V et al (2006) Transient and selective overexpression of dopamine D2 receptors in the striatum causes persistent abnormalities in prefrontal cortex functioning. Neuron 49:603–615
Kesner RP, Churchwell JC (2011) An analysis of rat prefrontal cortex in mediating executive function. Neurobiol Learn Mem 96:417–431
Koutsilieri E, Sopper S, Scheller C, ter Meulen V, Riederer P (2002) Parkinsonism in HIV dementia. J Neural Transm 109:767–775
Kumar AM, Ownby RL, Waldrop-Valverde D, Fernandez B, Kumar M (2011) Human immunodeficiency virus infection in the CNS and decreased dopamine availability: relationship with neuropsychological performance. J Neurovirol 17:26–40
Lee B, Groman S, London ED, Jentsch JD (2007) Dopamine D2/D3 receptors play a specific role in the reversal of a learned visual discrimination in monkeys. Neuropsychopharmacology 32:2125–2134
Maki PM, Martin-Thormeyer E (2009) HIV, cognition and women. Neuropsychol Rev 19:204–214
Maki PM, Cohen MH, Weber K, Little DM, Fornelli D, Rubin LH, Perschler P, Gould F, Martin E (2009) Impairments in memory and hippocampal function in HIV-positive vs HIV-negative women. Neurology 72:1661–1668
Manes F, Sahakian B, Clark L, Rogers R, Antoun N, Aitken M et al (2002) Decision-making processes following damage to the prefrontal cortex. Brain 125:624–639
Manly JJ, Smith C, Crystal HA, Richardson J, Golub ET, Greenblatt R, Robison E, Martin EM, Young M (2011) Relationship of ethnicity, age, education, and reading level to speed and executive function among HIV + and HIV- women: the Women’s interagency HIV study (WIHS) neurocognitive substudy. J Clin Exp Neuropsychol 33:853–863
Masliah E, Heaton RK, Marcotte TD, Ellis RJ, Wiley CA, Mallory M, Achim CL et al (1997) Dendritic injury is a pathological substrate for human immunodeficiency virus-related cognitive disorders. Ann Neurol 42:963–972
McAlonan K, Brown VJ (2003) Orbital prefrontal cortex mediates reversal learning and not attentional set shifting in the rat. Behav Brain Res 146:97–103
McGaughy J, Sarter M (1995) Behavioral vigilance in rats: task validation and effects of age, amphetamine, and benzodiazepine receptor ligands. Psychopharmacology 117:340–357
McGaughy J, Kaiser T, Sarter M (1996) Behavioral vigilance following infusions of 192 IgG-saporin into the basal forebrain: selectivity of the behavioral impairment and relation to cortical AChE-positive fiber density. Behav Neurosci 110:247–265
McGaughy J, Ross RS, Eichenbaum H (2008) Noradrenergic, but not cholinergic, deafferentation of prefrontal cortex impairs attentional set-shifting. Neuroscience 153:63–71
McLean SL, Beck JP, Woolley ML, Neill JC (2008) A preliminary investigation into the effects of antipsychotics on sub-chronic phencyclidine-induced deficits in attentional set-shifting in female rats. Behav Brain Res 189:152–158
Melrose RJ, Tinaz S, Castelo JMB, Courtney MG, Stern CE (2008) Compromised fronto-striatal functioning in HIV: an fMRI investigation of semantic event sequencing. Behav Brain Res 188:337–347
Midde NM, Huang X, Gomez AM, Booze RM, Zhan CG, Zhu J (2013) Mutation of tyrosine 470 of human dopamine transporter is critical for HIV-1 Tat-induced inhibition of dopamine transport and transporter conformational transitions. J NeuroImmune Pharmacol 8:975–987
Milstein JA, Lehmann O, Theobald DE, Dalley JW, Robbins TW (2007) Selective depletion of cortical noradrenaline by anti-dopamine beta-hydroxylase-saporin impairs attentional function and enhances the effects of Guanfacine in the rat. Psychopharmacology (Berlin) 190:51–63
Moore H, Fadel J, Sarter M, Bruno JP (1999) Role of accumbens and cortical dopamine receptors in the regulation of cortical acetylcholine release. Neuroscience 88:811–822
Moran LM, Aksenov MY, Booze RM, Webb KM, Mactutus CF (2012) Adolescent HIV-1 transgenic rats: evidence for dopaminergic alterations in behavior and neurochemistry revealed by methamphetamine challenge. Curr HIV Res 10:415–424
Moran LM, Booze RM, Mactutus CF (2013a) Time and time again: temporal processing demands implicate perceptual and gating deficits in the HIV-1 transgenic rat. J NeuroImmune Pharmacol 8:988–997
Moran LM, Booze RM, Webb KM, Mactutus CF (2013b) Neurobehavioral alterations in HIV-1 transgenic rats: evidence for dopaminergic dysfunction. Exp Neurol 239:139–147
O’Neill M, Brown VJ (2007) The effect of striatal dopamine depletion and the adenosine A2A antagonist KW-6002 on reversal learning in rats. Neurobiol Learn Mem 88:75–81
Parasuraman R, Davies DR (1977) A taxonomic analysis of vigilance performance. In: Mackie RR (ed) Vigilance: theory, operational performance, and physiological correlates. Springer, Plenum, pp 559–574
Peng JS, Vigorito M, Liu XQ, Zhou DJ, Wu XW, Chang SL (2010) The HIV-1 transgenic rat as a model for HIV-1 infected individuals on HAART. J Neuroimmunol 218:94–101
Pfefferbaum A, Rosenbloom MJ, Rohlfing T, Kemper CA, Deresinski S, Sullivan EV (2009) Frontostriatal fiber bundle compromise in HIV infection without dementia. AIDS 23:1977–1985
Reger M, Welsh R, Razani J, Martin DJ, Boone KB (2002) A meta-analysis of the neuropsychological sequelae of HIV infection. J Int Neuropsychol Soc 8:410–424
Reid W, Sadowska M, Denaro F, Rao S, Foulke J Jr, Hayes N, Jones O (2001) An HIV-1 transgenic rat that develops HIV-related pathology and immunologic dysfunction. Proc Natl Acad Sci 98:9271–9276
Ridley RM, Haystead TA, Baker HF (1981) An analysis of visual object reversal learning in the marmoset after amphetamine and haloperidol. Pharmacol Biochem Behav 14:345–351
Robinson ES, Eagle DM, Mar AC, Bari A, Banerjee G, Jiang X et al (2008) Similar effects of the selective noradrenaline reuptake inhibitor atomoxetine on three distinct forms of impulsivity in the rat. Neuropsychopharmacology 33:1028–1037
Rodefer JS, Nguyen TN, Karlsson JJ, Arnt J (2008) Reversal of subchronic PCP-induced deficits in attentional set shifting in rats by sertindole and a 5-HT6 receptor antagonist: comparison among antipsychotics. Neuropsychopharmacology 33:2657–2666
Royal W, Zhang L, Guo M, Jones O, Davis H, Bryant JL (2012) Immune activation, viral gene product expression and neurotoxicity in the HIV-1 transgenic rat. J Neuroimmunol 247:16–24
Sacktor N, McDermott MP, Marder K, Schifitto G, Selnes OA, McArthur JC, Stern Y, Albert S, Palumbo D, Kieburtz K, De Marcaida JA, Cohen B, Epstein L (2002) HIV-associated cognitive impairment before and after the advent of combination therapy. J Neurovirol 8:136–142
Scott JC, Woods SP, Vigil O, Heaton RK, Grant I, Ellis RJ, Marcotte TD (2011) Script generation of activities of daily living in HIV-associated neurocognitive disorders. J Int Neuropsychol Soc 17:740–745
Seu E, Jentsch JD (2009) Effect of acute and repeated treatment with desipramine or methylphenidate on serial reversal learning in rats. Neuropharmacology 57:665–672
Silvers JM, Aksenova MV, Aksenov MY, Mactutus CF, Booze RM (2007) Neurotoxicity of HIV-1 tat protein: involvement of D1 dopamine receptor. Neurotoxicology 28:1184–1190
Tait DS, Brown VJ, Farovik A, Theobald DE, Dalley JW, Robbins TW (2007) Lesions of the dorsal noradrenergic bundle impair attentional set-shifting in the rat. Eur J Neurosci 25:3719–3724
Tait DS, Marston HM, Shahid M, Brown VJ (2009) Asenapine restores cognitive flexibility in rats with medial prefrontal cortex lesions. Psychopharmacology 202:295–306
Thompson PM, Dutton RA, Hayashi KM, Toga AW, Lopez OL, Aizenstein HJ, Becker JT (2005) Thinning of the cerebral cortex visualized in HIV/AIDS reflects CD4(+) T lymphocyte decline. Proc Natl Acad Sci U S A 102:15647–15652
Tozzi V, Narciso P, Galgani S, Sette P, Balestra P, Gerace C, Pau FM et al (1993) Effects of zidovudine in 30 patients with mild to end-stage AIDS dementia complex. AIDS 7:683–692
Tunbridge EM, Bannerman DM, Sharp T, Harrison PJ (2004) Catechol-o-methyltransferase inhibition improves set-shifting performance and elevates stimulated dopamine release in the rat prefrontal cortex. J Neurosci 24:5331–5335
UNAIDS (2013) Global report: UNAIDS report on the global AIDS epidemic 2013. http://www.unaids.org/en/media/unaids/contentassets/documents/epidemiology/2013/gr2013/UNAIDS_Global_Report_2013_en.pdf
Vivithanaporn P, Heo G, Gamble J, Krentz HB, Hoke A, Gill MJ, Power C (2010) Neurologic disease burden in treated HIV/AIDS predicts survival a population-based study. Neurology 75:1150–1158
Wallace DR, Dodson S, Nath A, Booze RM (2006) Estrogen attenuates gp120-and tat(1–72)-induced oxidative stress and prevents loss of dopamine transporter function. Synapse 59:51–60
Wang GJ, Chang L, Volkow ND, Telang F, Logan J, Ernst T, Fowler JS (2004) Decreased brain dopaminergic transporters in HIV-associated dementia patients. Brain 127:2452–2458
Wang M, Ramos BP, Paspalas CD, Shu Y, Simen A, Duque A, Vijayraghavan S, Brennan A, Dudley A, Nou E, Mazer JA, McCormick DA, Arnsten AFT (2007) α2A-Adrenoceptors strengthen working memory networks by inhibiting cAMP-HCN channel signaling in prefrontal cortex. Cell 129:397–410
Watkins JM, Cool VA, Usner D, Stehbens JA, Nichols S, Loveland KA, Bordeaux JD, Donfield S, Asarnow RF, Nuechterlein KH (2000) Attention in HIV-infected children: results from the hemophilia growth and development study. J Int Neuropsychol Soc 6:443–454
Webb KM, Aksenov MY, Mactutus CF, Booze RM (2010) Evidence for developmental dopaminergic alterations in the human immunodeficiency virus-1 transgenic rat. J Neurovirol 16:168–173
Zhu J, Mactutus CF, Wallace DR, Booze RM (2009) HIV-1 Tat protein-induced rapid and reversible decrease in [H-3]dopamine uptake: dissociation of [H-3]dopamine uptake and [H-3]2 beta-carbomethoxy-3-beta-(4-fluorophenyl)tropane (WIN 35,428) binding in rat striatal synaptosomes. J Pharmacol Exp Ther 329:1071–1083
Zhu J, Ananthan S, Mactutus CF, Booze RM (2011) Recombinant human immunodeficiency virus-1 transactivator of transcription (1–86) allosterically modulates dopamine transporter activity. Synapse 65:1251–1254
Zmarowski A, Sarter M, Bruno JP (2005) NMDA and dopamine interactions in the nucleus accumbens modulate cortical acetylcholine release. Eur J Neurosci 22:1731–1740
Acknowledgments
This research was supported by the National Institute on Drug Abuse [RMB, Grant DA013137; CFM, Grant DA031604] and by the National Institute of Child Health and Human Development [CFM, Grant HD043680]. The authors thank Dr. Martin Sarter and Dr. Philip Bushnell for their expert consultation and generous sharing of their Med Associates computer programs.
Conflict of Interest
The authors declare that they have no conflict of interest.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Moran, L.M., Booze, R.M. & Mactutus, C.F. Modeling Deficits in Attention, Inhibition, and Flexibility in HAND. J Neuroimmune Pharmacol 9, 508–521 (2014). https://doi.org/10.1007/s11481-014-9539-z
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11481-014-9539-z