Altered hippocampal function and cytokine levels in a rat model of Gulf War illness.

AIMS: Gulf War illness (GWI) is a disorder affecting military personnel deployed in the Gulf War (GW) from 1990 to 1991. Here, we will use a rat model of GWI to evaluate hippocampal function and cytokine levels. MATERIALS AND METHODS: Rats were exposed to diethyltoluamide and permethrin via dermal absorption and pyridostigmine bromide via gavage with or without a 5-min restraint for 28 days. Immediate and delayed effects of GW chemical exposure were evaluated using electrophysiology to quantitate hippocampal function, behavioral tests to assess cognitive effects and biochemical assays to measure neurotransmitter and cytokine levels. KEY FINDINGS: Behavioral data revealed a statistically significant increase in motor activity at 3 months following completion of exposures, potentially indicating increased excitability, and/or restlessness. Electrophysiology data revealed statistically significant changes in paired pulse facilitation and input-output function of CA1 hippocampal neurons within 24 h and 3 months following completion of exposures. There was also a statistically significant reduction in the frequency of spontaneous firing activity of hippocampal neurons within 24 h following exposures. Naïve hippocampal slices directly incubated in GW chemicals also resulted in similar changes in electrophysiological parameters. Biochemical measurements revealed reduced hippocampal glutamate level at 3 months post-exposure. Furthermore, there was a statistically significant increase in plasma and hippocampal levels of IL-13, as well as decrease in plasma level of IL-1ß. SIGNIFICANCE: Our data support an effect on glutamate signaling within the hippocampus as indicated by changes in PPF and hippocampal level of glutamate, with some activation of T helper type 2 immune response.

Polarity and subfield specific effects of transcranial direct current stimulation on hippocampal plasticity.

An increasing number of studies using human subjects substantiate the use of transcranial direct current stimulation (tDCS) as a noninvasive approach to treat various neurological symptoms. tDCS has been tested in conditions from motor to cognition dysfunctions. Performance enhancement of healthy subjects using tDCS has also been explored. The underlying physiological mechanism for tDCS effects is hypothesized to be through changes in neuroplasticity and we have previously demonstrated that in vivo anodal tDCS can enhance neuroplasticity of hippocampal CA1 neurons. The purpose of this study was to determine whether the underlying electrophysiological changes that occur following in vivo tDCS are polarity specific. We also examined both the CA1 and CA3 regions of the hippocampus to determine whether the tDCS effects were subfield specific. We conducted in vivo tests of cathodal tDCS versus anodal tDCS on synaptic plasticity of CA1 and CA3 neurons of male rats. In each region we assessed long term potentiation (LTP), paired pulse facilitation (PPF) and long term depression (LTD). In the CA1 region, we found anodal tDCS significantly enhanced not only LTP and PPF, but also LTD. There was no statistical difference in LTP, PPF or LTD of hippocampal CA1 neurons resulting from cathodal tDCS. Neither anodal nor cathodal tDCS induced significant changes in neuroplasticity of hippocampal CA3 neurons. Results indicate that the effects of tDCS are subfield specific and polarity dependent with anodal tDCS having greater impact on synaptic activity in the rat hippocampus than cathodal tDCS.

Comparative electrophysiological evaluation of hippocampal function following repeated inhalation exposures to JP-8, Jet A, JP-5, and the synthetic Fischer Tropsch fuel.

Exposure to fuels continues to be a concern in both military and general populations. The aim of this study was to examine effects of in vivo rat repeated exposures to different types of jet fuel utilizing microelectrode arrays for comparative electrophysiological (EP) measurements in hippocampal slices. Animals were exposed to increasing concentrations of four jet fuels, Jet Propellant (JP)-8, Jet A, JP-5, or synthetic Fischer Tropsch (FT) fuel via whole-body inhalation for 20 d (6 hr/d, 5 d/week for 28 d) and synaptic transmission as well as behavioral performance were assessed. Our behavioral studies indicated no significant changes in behavioral performance in animals exposed to JP-8, Jet A, or JP-5. A significant deviation in learning pattern during the Morris water maze task was observed in rats exposed to the highest concentration of FT (2000 mg/m3). There were also significant differences in the EP profile of hippocampal neurons from animals exposed to JP-8, Jet A, JP-5, or FT compared to control air. However, these differences were not consistent across fuels or dose dependent. As expected, patterns of EP alterations in brain slices from JP-8 and Jet A exposures were more similar compared to those from JP-5 and FT. Further longitudinal investigations are needed to determine if these EP effects are transient or persistent. Such studies may dictate if and how one may use EP measurements to indicate potential susceptibility to neurological impairments, particularly those that result from inhalation exposure to chemicals or mixtures.

Modulating Hippocampal Plasticity with In Vivo Brain Stimulation.

Investigations into the use of transcranial direct current stimulation (tDCS) in relieving symptoms of neurological disorders and enhancing cognitive or motor performance have exhibited promising results. However, the mechanisms by which tDCS effects brain function remain under scrutiny. We have demonstrated that in vivo tDCS in rats produced a lasting effect on hippocampal synaptic plasticity, as measured using extracellular recordings. Ex vivo preparations of hippocampal slices from rats that have been subjected to tDCS of 0.10 or 0.25 mA for 30 min followed by 30 min of recovery time displayed a robust twofold enhancement in long-term potentiation (LTP) induction accompanied by a 30% increase in paired-pulse facilitation (PPF). The magnitude of the LTP effect was greater with 0.25 mA compared with 0.10 mA stimulations, suggesting a dose-dependent relationship between tDCS intensity and its effect on synaptic plasticity. To test the persistence of these observed effects, animals were stimulated in vivo for 30 min at 0.25 mA and then allowed to return to their home cage for 24 h. Observation of the enhanced LTP induction, but not the enhanced PPF, continued 24 h after completion of 0.25 mA of tDCS. Addition of the NMDA blocker AP-5 abolished LTP in both control and stimulated rats but maintained the PPF enhancement in stimulated rats. The observation of enhanced LTP and PPF after tDCS demonstrates that non-invasive electrical stimulation is capable of modifying synaptic plasticity. SIGNIFICANCE STATEMENT: Researchers have used brain stimulation such as transcranial direct current stimulation on human subjects to alleviate symptoms of neurological disorders and enhance their performance. Here, using rats, we have investigated the potential mechanisms of how in vivo brain stimulation can produce such effect. We recorded directly on viable brain slices from rats after brain stimulation to detect lasting changes in pattern of neuronal activity. Our results showed that 30 min of brain stimulation in rats induced a robust enhancement in synaptic plasticity, a neuronal process critical for learning and memory. Understanding such molecular effects will lead to a better understanding of the mechanisms by which brain stimulation produces its effects on cognition and performance.