Astrocyte-specific Ca2+ activity: Mechanisms of action, experimental tools, and roles in ethanol-induced dysfunction.

Astrocytes are a subtype of non-neuronal glial cells that reside in the central nervous system. Astrocytes have extensive peripheral astrocytic processes that ensheathe synapses to form the tripartite synapse. Through a multitude of pathways, astrocytes can influence synaptic development and structural maturation, respond to neuronal signals, and modulate synaptic transmission. Over the last decade, strong evidence has emerged demonstrating that astrocytes can influence behavioral outcomes in various animal models of cognition. However, the full extent of how astrocytes influence brain function is still being revealed. Astrocyte calcium (Ca2+) signaling has emerged as an important driver of astrocyte-neuronal communication allowing intricate crosstalk through mechanisms that are still not fully understood. Here, we will review the field's current understanding of astrocyte Ca2+ signaling and discuss the sophisticated state-of-the-art tools and approaches used to continue unraveling astrocytes' interesting role in brain function. Using the field of pre-clinical ethanol (EtOH) studies in the context of alcohol use disorder, we focus on how these novel approaches have helped to reveal an important role for astrocyte Ca2+ function in regulating EtOH consumption and how astrocyte Ca2+ dysfunction contributes to the cognitive deficits that emerge after EtOH exposure in a rodent model.

The effects of peri-adolescent alcohol use on the developing hippocampus.

Adolescence is a period of continued brain development. Regions of the brain, such as the hippocampus, continue to undergo refinement and maturation throughout adolescence and into early adulthood. Adolescence is also a time of heightened sensitivity to novelty and reward, which contribute to an increase in risk-taking behaviors including the use of drugs and alcohol. Importantly, binge drinking is highly prevalent among adolescents and emerging adults. The hippocampus which is important for the integration of emotion, reward, homeostasis, and memory is particularly vulnerable to the neurotoxic effects of alcohol. In this chapter, we cover the fundamentals of hippocampal neuroanatomy and the current state of knowledge of the acute and chronic effects of ethanol in adolescent humans and adolescent rodent models. We focus on the hippocampal-dependent behavioral, structural, and neurochemical changes and identify knowledge gaps in our understanding of age-dependent neurobiological effects of alcohol use.

Repeated, intermittent exposures to diisopropylfluorophosphate in rats: protracted effects on cholinergic markers, nerve growth factor-related proteins, and cognitive function.

Organophosphates (OPs) pose a constant threat to human health due to their widespread use as pesticides and their potential employment in military and terrorist attacks. The acute toxicity of OPs has been extensively studied; however, the consequences of prolonged or repeated exposure to levels of OPs that produce no overt signs of acute toxicity (i.e. subthreshold levels) are poorly understood. Further, there is clinical evidence that such repeated exposures to OPs lead to prolonged deficits in cognition, although the mechanism for this effect is unknown. In this study, the behavioral and neurochemical effects of repeated, intermittent, and subthreshold exposures to the alkyl OP, diisopropylfluorophosphate (DFP) were investigated. Rats were injected with DFP s.c. (dose range, 0.25-1.0 mg/kg) every other day over the course of 30 days, and then given a 2 week, DFP-free washout period. In behavioral experiments conducted at various times during the washout period, dose dependent decrements in a water maze hidden platform task and a spontaneous novel object recognition (NOR) procedure were observed, while prepulse inhibition of the acoustic startle response was unaffected. There were modest decreases in open field locomotor activity and grip strength (particularly during the DFP exposure period); however, rotarod performance and water maze swim speeds were not affected. After washout, DFP concentrations were minimal in plasma and brain, however, cholinesterase inhibition was still detectable in the brain. Moreover, the 1.0 mg/kg dose of DFP was associated with (brain region-dependent) alterations in nerve growth factor-related proteins and cholinergic markers. The results of this prospective animal study thus provide evidence to support two novel hypotheses: (1) that intermittent, subthreshold exposures to alkyl OPs can lead to protracted deficits in specific domains of cognition and (2) that such cognitive deficits may be related to persistent functional changes in brain neurotrophin and cholinergic pathways.

Repeated exposures to low-level chlorpyrifos results in impairments in sustained attention and increased impulsivity in rats.

Organophosphates such as chlorpyrifos (CPF) are among the most commonly used pesticides in the world. Therefore, it is not surprising that measurable levels of organophosphates (including CPF) are found in over 50% of fresh fruits, vegetables and grains that we consume and that approximately 80% of adults in the US have detectable levels of CPF metabolites in their urine. It is well known that acute exposure to organophosphates can cause cognitive deficits; however, the effects of daily or intermittent contact with low levels of organophosphates (often reflective of environmental exposures) are not well understood. The objective of this study was to determine if repeated low-level exposures to CPF impaired the performance of the 5-Choice Serial Reaction Time Task (5C-SRTT), an animal model of sustained attention. Adult rats were trained to stably perform the 5C-SRTT, then treated with vehicle or CPF 18.0 mg/kg daily for 14 consecutive days or every other day for 30 days. Behavioral testing occurred daily during the CPF-exposure period and throughout a 30 day washout period to assess recovery. All CPF-treated animals exhibited deficits in percent correct, an increase in omissions and premature responses without signs of impaired motivation or overt toxicity. Deficits in 5C-SRTT accuracy were apparent well into the 30 day washout period despite significant recovery of cholinesterase activity. These results indicate that repeated exposures to relatively low levels of chlorpyrifos lead to protracted impairments of sustained attention and an increase in impulsive behaviors in rats.