Experimental Ischemic Stroke Induces Secondary Bihemispheric White Matter Degeneration and Long-Term Cognitive Impairment.

Clinical studies have identified widespread white matter degeneration in ischemic stroke patients. However, contemporary research in stroke has predominately focused on the infarct and periinfarct penumbra regions. The involvement of white matter degeneration after ischemic stroke and its contribution to post-stroke cognitive impairment and dementia (PSCID) has remained less explored in experimental models. In this study, we examined the progression of locomotor and cognitive function up to 4 months after inducing ischemic stroke by middle cerebral artery occlusion in young adult rats. Despite evident ongoing locomotor recovery, long-term cognitive and affective impairments persisted after ischemic stroke, as indicated by Morris water maze, elevated plus maze, and open field performance. At 4 months after stroke, multimodal MRI was conducted to assess white matter degeneration. T2-weighted MRI (T2WI) unveiled bilateral cerebroventricular enlargement after ischemic stroke. Fluid Attenuated Inversion Recovery MRI (FLAIR) revealed white matter hyperintensities in the corpus callosum and fornix across bilateral hemispheres. A positive association between the volume of white matter hyperintensities and total cerebroventricular volume was noted in stroke rats. Further evidence of bilateral white matter degeneration was indicated by the reduction of fractional anisotropy and quantitative anisotropy at bilateral corpus callosum in diffusion-weighted MRI (DWI) analysis. Additionally, microglia and astrocyte activation were identified in the bilateral corpus callosum after stroke. Our study suggests that experimental ischemic stroke induced by MCAO in young rat replicate long-term cognitive impairment and bihemispheric white matter degeneration observed in ischemic stroke patients. This model provides an invaluable tool for unraveling the mechanisms underlying post-stroke secondary white matter degeneration and its contribution to PSCID.

Glutamate Provides Cytoprotective Effect for Astrocytes Against Ischemic Insult and Promotes Astrogliosis.

Glutamate-mediated excitotoxicity has been extensively explored as a therapeutic target for the development of potential treatments of neurological disorders including stroke. However, the effect of glutamate on astrocytes under pathological conditions has been less studied. Using primary astrocyte culture, we determined the effect of glutamate on astrocytes against ischemic insult. Glutamate provided a cytoprotective effect and acted as an alternative substrate for ATP production in primary astrocytes against oxygen glucose deprivation reoxygenation insult, which was blocked by glutamate uptake inhibition. The cytoprotective effect of glutamate appears to be astrocyte-specific, as glutamate dose-dependently induces cytotoxic action in murine hippocampal HT-22 cell line. Interestingly, the cytoprotective effect of glutamate against glucose deprivation was short-last, as no protection was observed after 3-day glucose deprivation. We determined the metabolic phenotype of primary astrocyte cultured in glucose or glutamate. Primary astrocytes cultured in glutamate displayed a different metabolic phenotype when compared to those cultured in glucose, evidenced by higher basal and maximal oxygen consumption rate (OCR), higher ATP production and proton leak-coupled OCR, as well as lower glycolysis. Furthermore, glutamate exposure resulted in astrocyte activation, evidenced by an increase in astrocyte size and GFAP expression. Our study demonstrated that glutamate exerts a dual effect on astrocytes under ischemic condition. Glutamate provides an alternative substrate for energy metabolism in the absence of glucose, thereby protecting astrocytes against ischemic insults. On the other hand, glutamate exposure induces astrogliosis. Modulation of glutamate uptake and metabolism in astrocytes may provide novel targets for alleviating ischemic injury and improving function recovery after ischemic stroke.

Metabolic Heterogeneity of Cerebral Cortical and Cerebellar Astrocytes.

Astrocytes play critical roles in regulating neuronal synaptogenesis, maintaining blood-brain barrier integrity, and recycling neurotransmitters. Increasing numbers of studies have suggested astrocyte heterogeneity in morphology, gene profile, and function. However, metabolic phenotype of astrocytes in different brain regions have not been explored. In this paper, we investigated the metabolic signature of cortical and cerebellar astrocytes using primary astrocyte cultures. We observed that cortical astrocytes were larger than cerebellar astrocytes, whereas cerebellar astrocytes had more and longer processes than cortical astrocytes. Using a Seahorse extracellular flux analyzer, we demonstrated that cortical astrocytes had higher mitochondrial respiration and glycolysis than cerebellar astrocytes. Cerebellar astrocytes have lower spare capacity of mitochondrial respiration and glycolysis as compared with cortical astrocytes. Consistently, cortical astrocytes have higher mitochondrial oxidation and glycolysis-derived ATP content than cerebellar astrocytes. In addition, cerebellar astrocytes have a fuel preference for glutamine and fatty acid, whereas cortical astrocytes were more dependent on glucose to meet energy demands. Our study indicated that cortical and cerebellar astrocytes display distinct metabolic phenotypes. Future studies on astrocyte metabolic heterogeneity and brain function in aging and neurodegeneration may lead to better understanding of the role of astrocyte in brain aging and neurodegenerative disorders.

Recurrent Transient Ischemic Attack Induces Neural Cytoskeleton Modification and Gliosis in an Experimental Model.

Transient ischemic attack (TIA) presents a high risk for subsequent stroke, Alzheimer's disease (AD), and related dementia (ADRD). However, the neuropathophysiology of TIA has been rarely studied. By evaluating recurrent TIA-induced neuropathological changes, our study aimed to explore the potential mechanisms underlying the contribution of TIA to ADRD. In the current study, we established a recurrent TIA model by three times 10-min middle cerebral artery occlusion within a week in rat. Neither permanent neurological deficit nor apoptosis was observed following recurrent TIA. No increase of AD-related biomarkers was indicated after TIA, including increase of tau hyperphosphorylation and ß-site APP cleaving enzyme 1 (BACE1). Neuronal cytoskeleton modification and neuroinflammation was found at 1, 3, and 7 days after recurrent TIA, evidenced by the reduction of microtubule-associated protein 2 (MAP2), elevation of neurofilament-light chain (NFL), and increase of glial fibrillary acidic protein (GFAP)-positive astrocytes and ionized calcium binding adaptor molecule 1 (Iba1)-positive microglia at the TIA-affected cerebral cortex and basal ganglion. Similar NFL, GFAP and Iba1 alteration was found in the white matter of corpus callosum. In summary, the current study demonstrated that recurrent TIA may trigger neuronal cytoskeleton change, astrogliosis, and microgliosis without induction of cell death at the acute and subacute stage. Our study indicates that TIA-induced neuronal cytoskeleton modification and neuroinflammation may be involved in the vascular contribution to cognitive impairment and dementia.

The Behavioral Response to Heat in the Common Bed Bug, Cimex lectularius (Hemiptera: Cimicidae).

The bed bug, Cimex lectularius L., is a common ectoparasite found to live among its vertebrate hosts. Antennal segments in bugs are critical for sensing multiple cues in the environment for survival. To determine whether the thermo receptors of bed bugs are located on their antennae; innovative bioassays were created to observe the choice between heated and unheated stimuli and to characterize the response of bugs to a heat source. Additionally, the effect of complete antenectomized segments on heat detection were evaluated. Heat, carbon dioxide, and moisture are cues that are found to activate bed bug behavior; a temperature at 38°C was used to assess the direction/degree at which the insect reacts to the change in distance from said stimulus. Using a lightweight spherical ball suspended by air through a vacuum tube, bed bugs and other insects are able to move in 360° while on a stationary point. Noldus EthoVision XT was used to capture video images and to track the bed bugs during 5-min bioassays. A bioassay was created using four Petri dish arenas to observe bed bug attraction to heat based on antennae segments at 40°C. The purpose of this study was to evaluate the effects of heat on complete antenectomized segments of the antennae. The results in this experiment suggest that bed bugs detect and are attracted to heat modulated by nutritional status. Learning the involvement of antennae segments in heat detection will help identify the location and role of thermoreceptors for bed bug host interaction.

A dose of experimental hormesis: When mild stress protects and improves animal performance.

The adaptive response characterized by a biphasic curve is known as hormesis. In a hormesis framework, exposure to low doses leads to protective and beneficial responses while exposures to high doses are damaging and detrimental. Comparative physiologists have studied hormesis for over a century, but our understanding of hormesis is fragmented due to rifts in consensus and taxonomic-specific terminology. Hormesis has been and is currently known by multiple names; preconditioning, conditioning, pretreatment, cross tolerance, adaptive homeostasis, and rapid stress hardening (mostly low temperature: rapid cold hardening). These are the most common names used to describe adaptive stress responses in animals. These responses are mechanistically similar, while having stress-specific responses, but they all can fall under the umbrella of hormesis. Here we review how hormesis studies have revealed animal performance benefits in response to changes in oxygen, temperature, ionizing radiation, heavy metals, pesticides, dehydration, gravity, and crowding. And how almost universally, hormetic responses are characterized by increases in performance that include either increases in reproduction, longevity, or both. And while the field can benefit from additional mechanistic work, we know that many of these responses are rooted in increases of antioxidants and oxidative stress protective mechanisms; including heat shock proteins. There is a clear, yet not fully elucidated, overlap between hormesis and the preparation for oxidative stress theory; which predicts part of the responses associated with hormesis. We discuss this, and the need for additional work into animal hormetic effects particularly focusing on the cost of hormesis.

Age-dependent microRNA control of synaptic plasticity in 22q11 deletion syndrome and schizophrenia.

The 22q11 deletion syndrome (22q11DS) is characterized by multiple physical and psychiatric abnormalities and is caused by the hemizygous deletion of a 1.5-3 Mb region of chromosome 22. It constitutes one of the strongest known genetic risks for schizophrenia; schizophrenia arises in as many as 30% of patients with 22q11DS during adolescence or early adulthood. A mouse model of 22q11DS displays an age-dependent increase in hippocampal long-term potentiation (LTP), a form of synaptic plasticity underlying learning and memory. The sarco(endo)plasmic reticulum Ca(2+) ATPase (SERCA2), which is responsible for loading Ca(2+) into the endoplasmic reticulum (ER), is elevated in this mouse model. The resulting increase in ER Ca(2+) load leads to enhanced neurotransmitter release and increased LTP. However, the mechanism by which the 22q11 microdeletion leads to SERCA2 overexpression and LTP increase has not been determined. Screening of multiple mutant mouse lines revealed that haploinsufficiency of Dgcr8, a microRNA (miRNA) biogenesis gene in the 22q11DS disease-critical region, causes age-dependent, synaptic SERCA2 overexpression and increased LTP. We found that miR-25 and miR-185, regulators of SERCA2, are depleted in mouse models of 22q11DS. Restoration of these miRNAs to presynaptic neurons rescues LTP in Dgcr8(+/-) mice. Finally, we show that SERCA2 is elevated in the brains of patients with schizophrenia, providing a link between mouse model findings and the human disease. We conclude that miRNA-dependent SERCA2 dysregulation is a pathogenic event in 22q11DS and schizophrenia.

Phosphatase and tensin homologue (PTEN) regulates synaptic plasticity independently of its effect on neuronal morphology and migration.

The tumour suppressor PTEN is the central negative regulator of the phosphatidylinositol 3-kinase (PI3K) signalling pathway, which mediates diverse processes in various tissues. In the nervous system, the PI3K pathway modulates proliferation, migration, cellular size, synaptic transmission and plasticity. In humans, neurological abnormalities such as autism, seizures and ataxia are associated with inherited PTEN mutations. In rodents, Pten loss during early development is associated with extensive deficits in neuronal migration and substantial hypertrophy of neurons and synaptic densities; however, whether its effect on synaptic transmission and plasticity is direct or mediated by structural abnormalities remains unknown. Here we analysed neuronal and synaptic structures and function in Pten-conditional knockout mice in which the gene was deleted from excitatory neurons postnatally. Using two-photon imaging, Golgi staining, immunohistochemistry, electron microscopy, and electrophysiological tools, we determined that Pten loss does not affect hippocampus development, neuronal or synaptic structures, or basal excitatory synaptic transmission. However, it does cause deficits in both major forms of synaptic plasticity, long-term potentiation and long-term depression, of excitatory synaptic transmission. These deficits coincided with impaired spatial memory, as measured in water maze tasks. Deletion of Pdk1, which encodes a positive downstream regulator of the PI3K pathway, rescued Pten-mediated deficits in synaptic plasticity but not in spatial memory. These results suggest that PTEN independently modulates functional and structural properties of hippocampal neurons and is directly involved in mechanisms of synaptic plasticity.

Effect of acute ethanol and acute allopregnanolone on spatial memory in adolescent and adult rats.

The effects of ethanol differ in adolescent and adult rats on a number of measures. The evidence of the effects of ethanol on spatial memory in adolescents and adults is equivocal. Whether adolescents are more or less sensitive to ethanol-induced impairment of spatial memory acquisition remains unclear; with regard to the effects of acute ethanol on spatial memory retrieval there is almost no research looking into any age difference. Thus, we examined the effects of acute ethanol on spatial memory in the Morris Watermaze in adolescents and adults. Allopregnanolone (ALLO) is a modulator of the GABA(A) receptor and has similar behavioral effects as ethanol. We sought to also determine the effects of allopreganolone on spatial memory in adolescent and adults. Male adolescent (post natal [PN]28-30) and adult (PN70-72) rats were trained in the Morris Watermaze for 6 days and acute doses of ethanol (saline, 1.5 and 2.0 g/kg) or ALLO (vehicle, 9 and 18 mg/kg) were administered on Day 7. A probe trial followed on Day 8. As expected, there were dose effects; higher doses of both ethanol and ALLO impaired spatial memory. However, in both the ethanol and ALLO conditions adolescents and adults had similar spatial memory impairments. The current results suggest that ethanol and ALLO both impair hippocampal-dependent spatial memory regardless of age in that once learning has occurred, ethanol or ALLO does not differentially impair the retrieval of spatial memory in adolescents and adults. Given the mixed results on the effect of ethanol on cognition in adolescent rats, additional research is needed to ascertain the factors critical for the reported differential results.

Parafoveal and foveal processing of abbreviations during eye fixations in reading: making a case for case.

The processing of abbreviations in reading was examined with an eye movement experiment. Abbreviations were of 2 distinct types: acronyms (abbreviations that can be read with the normal grapheme-phoneme correspondence [GPC] rules, such as NASA) and initialisms (abbreviations in which the GPCs are letter names, such as NCAA). Parafoveal and foveal processing of these abbreviations was assessed with the use of the boundary change paradigm (K. Rayner, 1975). Using this paradigm, previews of the abbreviations were either identical to the abbreviation (NASA or NCAA), orthographically legal (NUSO or NOBA), or illegal (NRSB or NRBA). The abbreviations were presented as capital letter strings within normal, predominantly lowercase sentences and also sentences in all capital letters such that the abbreviations would not be visually distinct. The results indicate that acronyms and initialisms undergo different processing during reading and that readers can modulate their processing based on low-level visual cues (distinct capitalization) in parafoveal vision. In particular, readers may be biased to process capitalized letter strings as initialisms in parafoveal vision when the rest of the sentence is normal, lowercase letters.

Dysregulation of presynaptic calcium and synaptic plasticity in a mouse model of 22q11 deletion syndrome.

The 22q11 deletion syndrome (22q11DS) is characterized by cognitive decline and increased risk of psychiatric disorders, mainly schizophrenia. The molecular mechanisms of neuronal dysfunction in cognitive symptoms of 22q11DS are poorly understood. Here, we report that a mouse model of 22q11DS, the Df(16)1/+ mouse, exhibits substantially enhanced short- and long-term synaptic plasticity at hippocampal CA3-CA1 synapses, which coincides with deficits in hippocampus-dependent spatial memory. These changes are evident in mature but not young animals. Electrophysiological, two-photon imaging and glutamate uncaging, and electron microscopic assays in acute brain slices showed that enhanced neurotransmitter release but not altered postsynaptic function or structure caused these changes. Enhanced neurotransmitter release in Df(16)1/+ mice coincided with altered calcium kinetics in CA3 presynaptic terminals and upregulated sarco(endo)plasmic reticulum calcium-ATPase type 2 (SERCA2). SERCA inhibitors rescued synaptic phenotypes of Df(16)1/+ mice. Thus, presynaptic SERCA2 upregulation may be a pathogenic event contributing to the cognitive symptoms of 22q11DS.

Investigation of ethanol-induced impairment of spatial memory in gamma2 heterozygous knockout mice.

GABA(A) receptors, the major inhibitory receptors in the mammalian central nervous system, are affected by a number of drug compounds, including ethanol. The pharmacological effects of certain drugs have been shown to be dependent upon specific GABA(A) receptor subunits. Because benzodiazepines and ethanol have similar effect signatures, it has been hypothesized that these drugs share the gamma2-containing GABA(A) receptors as a mechanism of action. To probe the involvement of the gamma2 subunit in ethanol's actions, spatial memory for the Morris water maze task was tested in gamma2 heterozygous knockout mice and wild type littermate controls following ethanol administration at the following doses: 0.0, 1.25, 1.75, and 2.25 g/kg. While baseline learning and memory were unaffected by reduction of gamma2 containing GABA(A) receptors, ethanol dose-dependently impaired spatial memory equally in gamma2 heterozygous knockouts and wild type littermate controls.

Acute mild footshock alters ethanol drinking and plasma corticosterone levels in C57BL/6J male mice, but not DBA/2J or A/J male mice.

Stress is an often-reported cause for alcohol consumption in humans. Acute intermittent footshock is a frequently used paradigm to produce stress in laboratory animals including mice. The effect produced by intermittent footshock stress on ethanol self-administration has been inconsistent: both increases and decreases in ethanol consumption have been reported. The current set of studies further investigates, in three commonly studied mouse strains, the effect of footshock stress on ethanol self-administration. Furthermore, the effect of footshock on plasma corticosterone levels was determined to investigate potential biochemical correlates. Adult male C57BL/6J, DBA/2J, and A/J mice were allowed to self-administer 10% (wt/vol) ethanol for 12 days in a standard 23-h two-bottle paradigm before receiving either 15 min of mild inescapable footshock or no footshock. Shock intensity was equal to the mean intensity at which each strain vocalized as previously determined. Following footshock, animals had the opportunity to self-administer ethanol for an additional 23 h. Separate animals were subjected to either footshock or no shock prior to collection of plasma for corticosterone. Mild footshock stress altered ethanol self-administration and increased plasma corticosterone levels in C57BL/6J mice. Footshock stress did not alter ethanol self-administration or plasma corticosterone levels in DBA/2J or A/J mice. These data demonstrate that mild footshock stress is a suboptimal method of modeling the stress-induced increases in ethanol consumption often reported by humans.

Mice with targeted genetic reduction of GABA(A) receptor alpha1 subunits display performance differences in Morris water maze tasks.

Recent research has begun to demonstrate that specific subunits of GABA(A) receptors may be involved in the normal expression of specific behaviors. The present research used mice with GABA(A) receptors whose alpha1 subunits contained mutations of serine 270 to histidine and leucine 277 to alanine in the TM2 region. The purpose was an attempt to examine the possible role that this particular subunit may have in learning the spatial and nonspatial version of the Morris water maze task. Mutant animals, compared to controls, displayed elevated levels of pool circling in both the spatial task and the nonspatial task. These results suggested that normal performance of the spatial and nonspatial water maze tasks may be dependent upon a natural alpha1 subunit array.

Knockin mice with ethanol-insensitive alpha1-containing gamma-aminobutyric acid type A receptors display selective alterations in behavioral responses to ethanol.

Despite the pervasiveness of alcohol (ethanol) use, it is unclear how the multiple molecular targets for ethanol contribute to its many behavioral effects. The function of GABA type A receptors (GABA(A)-Rs) is altered by ethanol, but there are multiple subtypes of these receptors, and thus far, individual subunits have not been definitively linked with specific behavioral actions. The alpha1 subunit of the GABA(A)-R is the most abundant alpha subunit in the brain, and the goal of this study was to determine the role of receptors containing this subunit in alcohol action. We designed an alpha1 subunit with serine 270 to histidine and leucine 277 to alanine mutations that was insensitive to potentiation by ethanol yet retained normal GABA sensitivity and constructed knockin mice containing this mutant subunit. Hippocampal slice recordings from these mice indicated that the mutant receptors were less sensitive to ethanol's potentiating effects. Behaviorally, we observed that mutant mice recovered more quickly from the motor-impairing effects of ethanol and etomidate, but not pentobarbital, and showed increased anxiolytic effects of ethanol. No differences were observed in ethanol-induced hypnosis, locomotor stimulation, cognitive impairment, or in ethanol preference and consumption. Overall, these studies demonstrate that the postsynaptic effects of ethanol at GABAergic synapses containing the alpha1 subunit are important for specific ethanol-induced behavioral effects.

Behavioral aspects of Angelman syndrome: a case control study.

Angelman syndrome (AS) is a rare congenital disorder characterized by impairments in intellectual, neurological and motor functioning and a postulated behavioral profile. This study compared behavioral characteristics of 62 individuals with genetically confirmed AS and 29 individuals with presumed AS from clinical features, with a control group of young persons with intellectual disability (ID) derived from an Australian epidemiological register. Twelve behavioral items from the developmental behavior checklist (DBC) were used for this comparison. The groups were matched for chronological age, gender, and level of ID. In the AS group, significant differences were found for 10 behaviors, with poor attention span and impulsivity being less common, and overactivity/restlessness, chewing or mouthing objects, eating non-food items, gorging food, food fads, fascination for water, hand flapping and sleep disturbance being more common. Interestingly, there was no difference in prevalence of unprovoked laughter. Comparison of the results of the genetically confirmed with the genetically unconfirmed AS cases showed no significant differences between individual behavior prevalence. These findings show that a "behavioral phenotype" of AS can be distinguished from others of similar level of ID, but it is different from that hitherto published. Abnormal food related behaviors, hyperactivity, fascination for water, hand flapping, and sleep disturbance should be included in a "behavioral phenotype" for AS. Apart from hyperactivity, "ADHD-type" behaviors are not more characteristic of AS than in ID generally. Therefore, the Consensus Criteria for the diagnosis of AS need to be reviewed.

Acute ethanol administration selectively impairs spatial memory in C57BL/6J mice.

It has been shown in rats that acute ethanol administration, via a single intraperitoneal injection, selectively impairs the memory of certain spatial tasks. It is unknown whether these same results can be produced in the C57BL/6J mouse strain. Male C57BL/6J mice were trained in a spatial task in the Morris water maze. After training, an ethanol test was administered in which each mouse was given an injection of one of four randomly assigned doses: ethanol, at a dose of 1.25, 1.75, or 2.25 g/kg, or a saline control dose that remained constant at 1.75 g/kg. Thirty minutes after injection, the mice were given the spatial task. Next, the same mice were given training for a nonspatial task in the Morris water maze. After training, another ethanol test was administered. Again, the mice were randomly assigned one of the aforementioned doses. Thirty minutes after injections, the mice were given the nonspatial task. Results from Study 1, by using latency, showed that acute ethanol administration selectively impaired spatial memory (P<.05) at 1.75 and 2.25 g/kg doses, yet it failed to significantly impair nonspatial memory except at the 2.25 g/kg dose. Results from Study 2, by using path lengths, showed similar effects, in that acute ethanol administration selectively impaired spatial memory (P<.05) at the 2.25 g/kg dose, yet it failed to impair nonspatial memory at any dose. These findings demonstrate that acute ethanol administration selectively impairs spatial memory in C57BL/6J mice.

Acute pulmonary toxicity following occupational exposure to a floor stain protector in the building industry in Switzerland.

BACKGROUND: Waterproofing agents are widely applied to leather and textile garments; they are also used as floor stain protectors by professionals. Acute respiratory injury is described in three cases of young healthy adults following occupational inhalation of a new waterproofing formulation containing an acrylate fluoropolymer. Within 1 or 2 h after exposure they developed a rapidly progressive dyspnoea; two of them had hypoxaemia and flu-like reactions. All patients improved with supportive treatment in a few days. The mechanism of toxicity is still under investigation, but experimental data suggest the role of this new acrylate fluoropolymer. CONCLUSION: Tilers should be warned against spraying floor stain repellents; there is also a need to make consumers aware that the spraying of waterproofing agents in a closed environment and concomitant smoking should be avoided.

Impairments in spatial learning and memory: ethanol, allopregnanolone, and the hippocampus.

Acute ethanol administration impairs performance in many cognitive tasks that are dependent on hippocampal function. For example, acute ethanol administration produces dose-dependent impairments in spatial learning. Ethanol also decreases the spatial specificity of hippocampal place cells. Such findings raise the possibility that ethanol affects learning and memory by altering, either directly or indirectly, neuronal activity in the hippocampus and related structures. Acute ethanol administration induces a dose- and time-dependent increase in brain concentration of the neuroactive steroid allopregnanolone. Allopregnanolone is a potent GABAA receptor agonist and produces effects similar to the effects produced by ethanol. Blockade of de novo biosynthesis of allopregnanolone alters many of ethanol's effects including ethanol-induced suppression of spontaneous activity in medial septum/diagonal band of Broca neurons and hippocampal pyramidal neurons. These findings suggest that ethanol-induced increases in allopregnanolone levels might play a central role in the effects of acute ethanol on cognitive processing and hippocampal function. The impact of ethanol on spatial cognitive processing and hippocampal function will be reviewed. In addition, the possibility that ethanol-induced changes in neuroactive steroid levels contribute to the impact of ethanol on spatial learning and hippocampal function will be explored.