The syndrome of cognitive and motor dysfunction observed after infection with HIV-1 has been designated HIV-1 associated neurocognitive disorder (HAND) (Antinori et al., 2007). The neuropathology associated with HAND includes encephalitis, microglial activation, chronic inflammation, neuronal loss, and decreased synaptic density (Garden et al., 2002). However, no effective treatment has been developed since the mechanisms leading to these cognitive deficiencies are not clearly understood. Various mechanisms have been proposed to explain these deficits, and implicate the HIV-1 coat protein, gp120 as an important factor mediating injury in the brain (Lipton, 1998). HIV-gp120 can act directly on neurons to induce neurotoxicity and apoptosis, and it can also activate the release of cytokines and cytotoxic factors (Bachis et al., 2006). Furthermore, it can bind and activate various receptors in the central nervous system (CNS) such as CD4, CXCR4, CCR5, and nicotinic acetylcholine receptors (Bracci et al., 1992; Liu et al., 2000; Rock et al., 2008). Nicotinic acetylcholine receptors have various subtypes, several of which are expressed in the CNS. The homopentameric receptor α7 (α7-nAChR) is widely expressed throughout the CNS and has been shown to help control cognitive functions (Court et al., 2000; Gahring and Rogers, 2005). This receptor is also associated with other neurocognitive diseases such as Alzheimer and Parkinson’s, and even though its role in HAND has been suggested (Bracci et al., 1992; Giunta et al., 2004; Rock et al., 2008), it has not been elucidated until recently in a study by Ballester et al., 2012. The purpose of this dissertation is to study the role of α7-nAChRs on gp120-neurotoxicity using an in vivo model. Chapter 2 recapitulates findings from a study on an in vitro setting (Ballester et al., 2012), where we described a model to account for the gp120-neurotoxity based on the regulation of α7-nAChRs. Additionally, the use of the gp120-transgenic mice (gp120- tg), an in vivo model, to study this mechanism was also demonstrated. Since α7-nAChR are highly permeable to calcium, we hypothesized that activation of the receptor on upregulated cells would lead to higher calcium concentrations sufficient to trigger apoptosis, results described on Chapter 3. Lastly, on Chapter 4 we studied gp120-tg performance on paradigms dependent on striatal function to correlate neuronal damage with behavioral changes. We demonstrate that gp120-tg do exhibit both locomotor and cognitive deficits. Moreover, treatment with antagonist of α7-nAChRs improved locomotor deficiencies on gp120-tg mice. We conclude with the statement that the α7- nAChR upregulation is a model to account for neurodegeneration in the brain, summarized on Chapter 5 and future perspectives and directions for this dissertation are detailed on Chapter 6.