Matching Items (3)
- All Subjects: RASopathies
- All Subjects: Glia
- Creators: Olive, M. Foster
- Creators: Hilbert, Alexander Robert
- Creators: Roose, Cassandra Ann
Use of psychostimulants, such as cocaine, is associated with an increased risk of human immunodeficiency virus (HIV) infection. Dopaminergic signaling within the nucleus accumbens (NAc) is critically implicated in both disease states, mediating the addictive and reinforcing effects of cocaine and perpetuating HIV replication throughout the central nervous system (CNS). Cocaine and HIV induce neurobehavioral deficits separately; however, little is known regarding how they interact to dysregulate neuroimmune function or how this impacts relapse vulnerability. We have previously shown that inhibition of dopamine D3 receptor (D3R) signaling using MC-25-41, a novel and highly selective D3R partial agonist, attenuates cocaine-seeking behavior. Here, we sought to characterize changes in neuroimmune function in a rat model of combined HIV and cocaine use disorders across abstinence and examined the therapeutic efficacy of MC-25-41 in the presence of this comorbidity. Male rats were systemically treated with the HIV protein gp120 after establishing a history of cocaine self-administration and then, following 21 days of abstinence, were administered a systemic injection of MC-25-41 (10 mg/kg) prior to cue reactivity testing. Glial fibrillary acidic protein (GFAP) and ionized calcium-binding adapter molecule 1 (Iba1) immunoreactivity were analyzed after 5 or 21 days of cocaine abstinence as an index of glial cell levels. We demonstrate that inhibition of D3R signaling significantly attenuates cue-induced cocaine seeking among control rats but not gp120-exposed rats. Moreover, we show that NAc core GFAP and Iba1 expression is impaired by 5 days of abstinence, which persists into protracted abstinence and cue reactivity testing. However, we also demonstrate that neither gp120 nor D3R inhibition significantly altered NAc core GFAP or Iba1 expression. Altogether, these results reveal significant changes in glial cell function across cocaine abstinence and unique behavioral interactions with gp120 may inhibit the effectiveness of medication regimens, which highlights the need to consider these comorbidities when treating HIV infection.
The RAS/MAPK (RAS/Mitogen Activated Protein Kinase) pathway is a highly conserved, canonical signaling cascade that is highly involved in cellular growth and proliferation as well as cell migration. As such, it plays an important role in development, specifically in development of the nervous system. Activation of ERK is indispensable for the differentiation of Embryonic Stem Cells (ESC) into neuronal precursors (Li z et al, 2006). ERK signaling has also shown to mediate Schwann cell myelination of the peripheral nervous system (PNS) as well as oligodendrocyte proliferation (Newbern et al, 2011). The class of developmental disorders that result in the dysregulation of RAS signaling are known as RASopathies. The molecular and cell-specific consequences of these various pathway mutations remain to be elucidated. While there is evidence for altered DNA transcription in RASopathies, there is little work examining the effects of the RASopathy-linked mutations on protein translation and post-translational modifications in vivo. RASopathies have phenotypic and molecular similarities to other disorders such as Fragile X Syndrome (FXS) and Tuberous Sclerosis (TSC) that show evidence of aberrant protein synthesis and affect related pathways. There are also well-defined downstream RAS pathway elements involved in translation. Additionally, aberrant corticospinal axon outgrowth has been observed in disease models of RASopathies (Xing et al, 2016). For these reasons, this present study examines a subset of proteins involved in translation and translational regulation in the context of RASopathy disease states. Results indicate that in both of the tested RASopathy model systems, there is altered mTOR expression. Additionally the loss of function model showed a decrease in rps6 activation. This data supports a role for the selective dysregulation of translational control elements in RASopathy models. This data also indicates that the primary candidate mechanism for control of altered translation in these modes is through the altered expression of mTOR.
Rasopathies are a family of developmental syndromes that exhibit craniofacial abnormalities, cognitive disabilities, developmental delay and increased risk of cancer. However, little is known about the pathogenesis of developmental defects in the nervous system. Frequently, gain-of-function mutations in the Ras/Raf/MEK/ERK cascade (aka ERK/MAPK) are associated with the observed pathogenesis. My research focuses on defining the relationship between increased ERK/MAPK signaling and its effects on the nervous system, specifically in the context of motor learning. Motor function depends on several neuroanatomically distinct regions, especially the spinal cord, cerebellum, striatum, and cerebral cortex. We tested whether hyperactivation of ERK/MAPK specifically in the cortex was sufficient to drive changes in motor function. We used a series of genetically modified mouse models and cre-lox technology to hyperactivate ERK/MAPK in the cerebral cortex. Nex:Cre/NeuroD6:Cre was employed to express a constitutively active MEK mutation throughout all layers of the cerebral cortex from an early stage of development. RBP4:Cre, caMEK only exhibited hyper activation in cortical glutamatergic neurons responsible for cortical output (neurons in layer V of the cerebral cortex). First, the two mouse strains were tested in an open field paradigm to assess global locomotor abilities and overall fitness for fine motor tasks. Next, a skilled motor reaching task was used to evaluate motor learning capabilities. The results show that Nex:Cre/NeuroD6:Cre, caMEK mutants do not learn the motor reaching task, although they performed normally on the open field task. Preliminary results suggest RBP4:Cre, caMEK mutants exhibit normal locomotor capabilities and a partial lack of learning. The difference in motor learning capabilities might be explained by the extent of altered connectivity in different regions of the corticospinal tract. Once we have identified the neuropathological effects of various layers in the cortex we will be able to determine whether therapeutic interventions are sufficient to reverse these learning defects.