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Methamphetamine (Meth) is a powerful illicit psychostimulant, widely used for recreational purposes. Besides disrupting the monoaminergic system and promoting oxidative brain damage, Meth also causes neuroinflammation, contributing to synaptic dysfunction and behavioral deficits. Aberrant activation of microglia, the largest myeloid cell population in the brain, is a common feature in neurological disorders triggered by neuroinflammation. In this study, we investigated the mechanisms underlying the aberrant activation of microglia elicited by Meth in the adult mouse brain. We found that binge Meth exposure caused microgliosis and disrupted risk assessment behavior (a feature that usually occurs in individuals who abuse Meth), both of which required astrocyte-to-microglia crosstalk. Mechanistically, Meth triggered a detrimental increase of glutamate exocytosis from astrocytes (in a process dependent on TNF production and calcium mobilization), promoting microglial expansion and reactivity. Ablating TNF production, or suppressing astrocytic calcium mobilization, prevented Meth-elicited microglia reactivity and re-established risk assessment behavior as tested by elevated plus maze (EPM). Overall, our data indicate that glial crosstalk is critical to relay alterations caused by acute Meth exposure.

Microglia, the largest population of brain immune cells, continuously interact with synapses to maintain brain homeostasis. In this study, we use conditional cell-specific gene targeting in mice with multi-omics approaches and demonstrate that the RhoGTPase Rac1 is an essential requirement for microglia to sense and interpret the brain microenvironment. This is crucial for microglia-synapse crosstalk that drives experience-dependent plasticity, a fundamental brain property impaired in several neuropsychiatric disorders. Phosphoproteomics profiling detects a large modulation of RhoGTPase signaling, predominantly of Rac1, in microglia of mice exposed to an environmental enrichment protocol known to induce experience-dependent brain plasticity and cognitive performance. Ablation of microglial Rac1 affects pathways involved in microglia-synapse communication, disrupts experience-dependent synaptic remodeling, and blocks the gains in learning, memory, and sociability induced by environmental enrichment. Our results reveal microglial Rac1 as a central regulator of pathways involved in the microglia-synapse crosstalk required for experience-dependent synaptic plasticity and cognitive performance.

Published ahead of print November 25, 2014.

The amygdala is a brain region that is known to be implicated in the development of behavioral sensitization to cocaine. This area is often related to conditioned associations, stress responses, and anxiety; and these behaviors are usually posited to be due to altered dopamine levels. This study aimed to evaluate the effects of neonatal exposure to cocaine on the levels of neurotransmitters in the amygdala of developing rats and to relate these levels with open-field observations, mainly rearing behavior, that is regarded to reflect emotional components. Male and female Wistar rats were given 15 mg of cocaine hydrochloridekg body weight, subcutaneously, in two daily doses, from postnatal day 1 (PND1) to PND30. Controls were given 0.9 saline. Open-field activity was registered on PND14, 21, and 30 in three sessions of 15 min each. In PND30, rats were decapitated, and the amygdala dissected from both brain hemispheres and processed for determination of dopamine (DA) and metabolites by high-performance liquid chromatography with electrochemical detection (HPLC-EC). Results show that in PND14 and 21 all registered activity behaviors were increased in male and female cocaine-exposed animals. In PND30, there was a significant decrease in rearing and in global activity in the group exposed to cocaine, and DA levels were significantly decreased in the amygdala of the same group. No differences were found between the left and right amygdala. These results suggest that chronic neonatal cocaine administration leads to depletion of DA levels in the amygdala, which is consistent with previous findings. Furthermore, the lower levels of DA are associated with decreased rearing behavior, which may indicate emotional depression. These results can help to clarify the role of amygdala in cocaine-induced behavioral sensitization in the developing rat.

The visual system of rodents is affected if exposure to drugs, e.g., cocaine, occurs during prenatal or early postnatal development. This study aims to evaluate, in an experimental model of neonatal exposure to cocaine in the rat, the immunocytochemical expression of tyrosine hydroxylase in the retina and the levels of different neurotransmitters and its metabolites. Male Wistar rats were given 15 mg cocaine hydrochloride/kg body weight/day, subcutaneously, in two daily doses, from the day after birth (PND1) to PND6, 13, and 29. Controls were given 0.9% saline. Groups of rats were perfused at PND7, 14, and 30 with fixative, and the retinas were processed as wholemounts, and immunostained with the antibody anti‐TH. Other groups were decapitated, and the retinas were dissected and processed by high performance liquid chromatography with electrochemical detection (HPLC‐EC) for determination of dopamine and metabolites (DOPAC and HVA). A reduction in the retinal surface area was detected in the PND30 cocaine group, and a decrease in the density of the small TH‐IR cells was found in the PND14 cocaine group although not reaching significant levels. The other quantitative parameters did not differ between the control and cocaine groups. The levels of neurotransmitters did not significantly differ between the groups at any age. These results show a differential vulnerability of the dopaminergic system of rats exposed neonatally to cocaine when compared with the effects found after prenatal exposure to the same drug.

Binge drinking may cause anxiety by triggering microglia to destroy excitatory synapses.

Nervous tissue homeostasis requires the regulation of microglia activity. Using conditional gene targeting in mice, we demonstrate that genetic ablation of the small GTPase Rhoa in adult microglia is sufficient to trigger spontaneous microglia activation, producing a neurological phenotype (including synapse and neuron loss, impairment of long-term potentiation [LTP], formation of β-amyloid plaques, and memory deficits). Mechanistically, loss of Rhoa in microglia triggers Src activation and Src-mediated tumor necrosis factor (TNF) production, leading to excitotoxic glutamate secretion. Inhibiting Src in microglia Rhoa-deficient mice attenuates microglia dysregulation and the ensuing neurological phenotype. We also find that the Rhoa/Src signaling pathway is disrupted in microglia of the APP/PS1 mouse model of Alzheimer disease and that low doses of Aβ oligomers trigger microglia neurotoxic polarization through the disruption of Rhoa-to-Src signaling. Overall, our results indicate that disturbing Rho GTPase signaling in microglia can directly cause neurodegeneration.