Effects of Acute or Chronic Ethanol Exposure during Adolescence on Behavioral Inhibition and Efficiency in a Modified Water Maze Task

Ethanol is well known to adversely affect frontal executive functioning, which continues to develop throughout adolescence and into young adulthood. This is also a developmental window in which ethanol is misused by a significant number of adolescents. We examined the effects of acute and chronic ethanol exposure during adolescence on behavioral inhibition and efficiency using a modified water maze task. During acquisition, rats were trained to find a stable visible platform onto which they could escape. During the test phase, the stable platform was converted to a visible floating platform (providing no escape) and a new hidden platform was added in the opposite quadrant. The hidden platform was the only means of escape during the test phase. In experiment 1, adolescent animals received ethanol (1.0g/kg) 30min before each session during the test phase. In experiment 2, adolescent animals received chronic intermittent ethanol (5.0g/kg) for 16 days (PND30 To PND46) prior to any training in the maze. At PND72, training was initiated in the same modified water maze task. Results from experiment 1 indicated that acute ethanol promoted behavioral disinhibition and inefficiency. Experiment 2 showed that chronic intermittent ethanol during adolescence appeared to have no lasting effect on behavioral disinhibition or new spatial learning during adulthood. However, chronic ethanol did promote behavioral inefficiency. In summary, results indicate that ethanol-induced promotion of perseverative behavior may contribute to the many adverse behavioral sequelae of alcohol intoxication in adolescents and young adults. Moreover, the long-term effect of adolescent chronic ethanol exposure on behavioral efficiency is similar to that observed after chronic exposure in humans

Regional-Specific Effects of Ovarian Hormone Loss on Synaptic Plasticity in Adult Human APOE Targeted Replacement Mice

The human apolipoprotein ε4 allele (APOE4) has been implicated as one of the strongest genetic risk factors associated with Alzheimer’s disease (AD) and in influencing normal cognitive functioning. Previous studies have demonstrated that mice expressing human apoE4 display deficits in behavioral and neurophysiological outcomes compared to those with apoE3. Ovarian hormones have also been shown to be important in modulating synaptic processes underlying cognitive function, yet little is known about how their effects are influenced by apoE. In the current study, female adult human APOE targeted replacement (TR) mice were utilized to examine the effects of human APOE genotype and long-term ovarian hormone loss on synaptic plasticity in limbic regions by measuring dendritic spine density and electrophysiological function. No significant genotype differences were observed on any outcomes within intact mice. However, there was a significant main effect of genotype on total spine density in apical dendrites in the hippocampus, with post-hoc t-tests revealing a significant reduction in spine density in apoE3 ovariectomized (OVX) mice compared to sham operated mice. There was also a significant main effect of OVX on the magnitude of LTP, with post-hoc t-tests revealing a decrease in apoE3 OVX mice relative to sham. In contrast, apoE4 OVX mice showed increased synaptic activity relative to sham. In the lateral amygdala, there was a significant increase in total spine density in apoE4 OVX mice relative to sham. This increase in spine density was consistent with a significant increase in spontaneous excitatory activity in apoE4 OVX mice. These findings suggest that ovarian hormones differentially modulate synaptic integrity in an apoE-dependent manner within brain regions that are susceptible to neurophysiological dysfunction associated with AD

Long-Term Effects of Chronic Intermittent Ethanol Exposure in Adolescent and Adult Rats: Radial-Arm Maze Performance and Operant Food Reinforced Responding

Background: Adolescence is not only a critical period of late-stage neurological development in humans, but is also a period in which ethanol consumption is often at its highest. Given the prevalence of ethanol use during this vulnerable developmental period we assessed the long-term effects of chronic intermittent ethanol (CIE) exposure during adolescence, compared to adulthood, on performance in the radial-arm maze (RAM) and operant food-reinforced responding in male rats. Methodology/Principal Findings: Male Sprague Dawley rats were exposed to CIE (or saline) and then allowed to recover. Animals were then trained in either the RAM task or an operant task using fixed- and progressive- ratio schedules. After baseline testing was completed all animals received an acute ethanol challenge while blood ethanol levels (BECs) were monitored in a subset of animals. CIE exposure during adolescence, but not adulthood decreased the amount of time that animals spent in the open portions of the RAM arms (reminiscent of deficits in risk-reward ntegration) and rendered animals more susceptible to the acute effects of an ethanol challenge on working memory tasks. The operant food reinforced task showed that these effects were not due to altered food motivation or to differential sensitivity to the nonspecific performance-disrupting effects of ethanol. However, CIE pre-treated animals had lower BEC levels than controls during the acute ethanol challenges indicating persistent pharmacokinetic tolerance to ethanol after the CIE treatment. There was little evidence of enduring effects of CIE alone on traditional measures of spatial and working memory. Conclusions/Significance: These effects indicate that adolescence is a time of selective vulnerability to the long-term effects of repeated ethanol exposure on neurobehavioral function and acute ethanol sensitivity. The positive and negative findings reported here help to further define the nature and extent of the impairments observed after adolescent CIE and provide direction for future research

Adolescent Intermittent Alcohol Exposure: Deficits in Object Recognition Memory and Forebrain Cholinergic Markers

The long-term effects of intermittent ethanol exposure during adolescence (AIE) are of intensive interest and investigation. The effects of AIE on learning and memory and the neural functions that drive them are of particular interest as clinical findings suggest enduring deficits in those cognitive domains in humans after ethanol abuse during adolescence. Although studies of such deficits after AIE hold much promise for identifying mechanisms and therapeutic interventions, the findings are sparse and inconclusive. The present results identify a specific deficit in memory function after AIE and establish a possible neural mechanism of that deficit that may be of translational significance. Male rats (starting at PND-30) received exposure to AIE (5g/kg, i.g.) or vehicle and were allowed to mature into adulthood. At PND-71, one group of animals was assessed using the spatial-temporal object recognition (stOR) test to evaluate memory function. A separate group of animals was used to assess the density of cholinergic neurons in forebrain areas Ch1-4 using immunohistochemistry. AIE exposed animals manifested deficits in the temporal component of the stOR task relative to controls, and a significant decrease in the number of ChAT labeled neurons in forebrain areas Ch1-4. These findings add to the growing literature indicating long-lasting neural and behavioral effects of AIE that persist into adulthood and indicate that memory-related deficits after AIE depend upon the tasks employed, and possibly their degree of complexity. Finally, the parallel finding of diminished cholinergic neuron density suggests a possible mechanism underlying the effects of AIE on memory and hippocampal function as well as possible therapeutic or preventive strategies for AIE

Effect of sub-chronic intermittent ethanol exposure on spatial learning and ethanol sensitivity in adolescent and adult rats

It has become clear that adolescence is a period of distinct responsiveness to the acute effects of ethanol on learning and other cognitive functions. However, the effects of repeated intermittent ethanol exposure during adolescence on learning and cognition are less well studied, and other effects of repeated ethanol exposure such as withdrawal and chronic tolerance complicate such experiments. Moreover, few studies have compared the effects of repeated ethanol exposure during adolescence and adulthood, and they have yielded mixed outcomes that may be related to methodological differences and/or secondary effects of ethanol on behavioral performance. One emerging question is whether relatively brief intermittent ethanol exposure (i.e., sub-chronic exposure) during adolescence or adulthood might alter learning at a time after exposure when chronic tolerance would be expected, and whether tolerance to the cognitive effects of ethanol might influence the effect of ethanol on learning at that time. To address this, male adolescent and adult rats were pre-treated with sub-chronic daily ethanol (five doses [4.0 g/kg, i.p.] or saline at 24-h intervals, across 5 days). Two days after the last pre-exposure, spatial learning was assessed on 4 consecutive days using the Morris water maze. Half of the animals from each treatment cell received ethanol (2.0 g/kg, i.p.) 30 min prior to each testing session and half of the animals received saline. Ethanol pre-exposure altered water maze performance in adolescent animals but not in adults, and acute ethanol exposure impaired learning in animals of both ages independent of pre-exposure condition. There was no evidence of cognitive tolerance in animals of either age group. These results indicate that a relatively short period of intermittent ethanol exposure during adolescence, but not adulthood, alters baseline water maze performance shortly after pre-exposure and does not induce cognitive tolerance to the effects of ethanol in either age group

A blood-based biomarker panel to risk-stratify mild traumatic brain injury

<div><p>Mild traumatic brain injury (TBI) accounts for the vast majority of the nearly two million brain injuries suffered in the United States each year. Mild TBI is commonly classified as complicated (radiographic evidence of intracranial injury) or uncomplicated (radiographically negative). Such a distinction is important because it helps to determine the need for further neuroimaging, potential admission, or neurosurgical intervention. Unfortunately, imaging modalities such as computed tomography (CT) and magnetic resonance imaging (MRI) are costly and not without some risk. The purpose of this study was to screen 87 serum biomarkers to identify a select panel of biomarkers that would predict the presence of intracranial injury as determined by initial brain CT. Serum was collected from 110 patients who sustained a mild TBI within 24 hours of blood draw. Two models were created. In the broad inclusive model, 72kDa type IV collagenase (MMP-2), C-reactive protein (CRP), creatine kinase B type (CKBB), fatty acid binding protein—heart (hFABP), granulocyte-macrophage colony-stimulating factor (GM-CSF) and malondialdehyde modified low density lipoprotein (MDA-LDL) significantly predicted injury visualized on CT, yielding an overall c-statistic of 0.975 and a negative predictive value (NPV) of 98.6. In the parsimonious model, MMP-2, CRP, and CKBB type significantly predicted injury visualized on CT, yielding an overall c-statistic of 0.964 and a negative predictive value (NPV) of 97.2. These results suggest that a serum based biomarker panel can accurately differentiate patients with complicated mild TBI from those with uncomplicated mild TBI. Such a panel could be useful to guide early triage decisions, including the need for further evaluation or admission, especially in those environments in which resources are limited.</p></div

Effect of sub-chronic intermittent ethanol exposure on spatial learning and ethanol sensitivity in adolescent and adult rats

It has become clear that adolescence is a period of distinct responsiveness to the acute effects of ethanol on learning and other cognitive functions. However, the effects of repeated intermittent ethanol exposure during adolescence on learning and cognition are less well studied, and other effects of repeated ethanol exposure such as withdrawal and chronic tolerance complicate such experiments. Moreover, few studies have compared the effects of repeated ethanol exposure during adolescence and adulthood, and they have yielded mixed outcomes that may be related to methodological differences and/or secondary effects of ethanol on behavioral performance. One emerging question is whether relatively brief intermittent ethanol exposure (i.e., sub-chronic exposure) during adolescence or adulthood might alter learning at a time after exposure when chronic tolerance would be expected, and whether tolerance to the cognitive effects of ethanol might influence the effect of ethanol on learning at that time. To address this, male adolescent and adult rats were pre-treated with sub-chronic daily ethanol (five doses [4.0 g/kg, i.p.] or saline at 24-h intervals, across 5 days). Two days after the last pre-exposure, spatial learning was assessed on 4 consecutive days using the Morris water maze. Half of the animals from each treatment cell received ethanol (2.0 g/kg, i.p.) 30 min prior to each testing session and half of the animals received saline. Ethanol pre-exposure altered water maze performance in adolescent animals but not in adults, and acute ethanol exposure impaired learning in animals of both ages independent of pre-exposure condition. There was no evidence of cognitive tolerance in animals of either age group. These results indicate that a relatively short period of intermittent ethanol exposure during adolescence, but not adulthood, alters baseline water maze performance shortly after pre-exposure and does not induce cognitive tolerance to the effects of ethanol in either age group

A blood-based biomarker panel to risk-stratify mild traumatic brain injury - Table 1

<p>A blood-based biomarker panel to risk-stratify mild traumatic brain injury</p> - Table

Receiver Operating Characteristic curves (ROC).

<p>ROC representing models used for discriminating complicated (CT+) versus uncomplicated (CT-) mTBI. Panel A: Broad Model (blue line, AUC = 0.975); Validated Broad Model (green line, AUC = 0.874); Covariates alone (black line, AUC = 0.882). Panel B: Parsimonious Model (red line, AUC = 0.964); Validated Parsimonious Model (green line, AUC = 0.956); Covariates alone (black line, AUC = 0.882).</p