Adult-born neurons maintain hippocampal cholinergic inputs and support working memory during aging.

Adult neurogenesis is reduced during aging and impaired in disorders of stress, memory, and cognition though its normal function remains unclear. Moreover, a systems level understanding of how a small number of young hippocampal neurons could dramatically influence brain function is lacking. We examined whether adult neurogenesis sustains hippocampal connections cumulatively across the life span. Long-term suppression of neurogenesis as occurs during stress and aging resulted in an accelerated decline in hippocampal acetylcholine signaling and a slow and progressing emergence of profound working memory deficits. These deficits were accompanied by compensatory reorganization of cholinergic dentate gyrus inputs with increased cholinergic innervation to the ventral hippocampus and recruitment of ventrally projecting neurons by the dorsal projection. While increased cholinergic innervation was dysfunctional and corresponded to overall decreases in cholinergic levels and signaling, it could be recruited to correct the resulting memory dysfunction even in old animals. Our study demonstrates that hippocampal neurogenesis supports memory by maintaining the septohippocampal cholinergic circuit across the lifespan.  It also provides a systems level explanation for the progressive nature of memory deterioration during normal and pathological aging and indicates that the brain connectome is malleable by experience.

Adolescent Binge-Type Ethanol Exposure in Rats Mirrors Age-Related Cognitive Decline by Suppressing Cholinergic Tone and Hippocampal Neurogenesis.

Heavy alcohol consumption followed by periods of abstinence (i.e., binge drinking) during adolescence is a concern for both acute and chronic health issues. Persistent brain damage after adolescent intermittent ethanol exposure in rodents, a model of binge drinking, includes reduced hippocampal neurogenesis and a loss of neurons in the basal forebrain that express the cholinergic phenotype. The circuit formed between those regions, the septohippocampal pathway, is critical for learning and memory. Furthermore, this circuit is also altered during the aging process. Thus, we examined whether pathology in septohippocampal circuit and impairments in spatial behaviors are amplified during aging following adolescent intermittent ethanol exposure. Female and male rats were exposed to intermittent intragastric gavage of water (control) or 20% ethanol (dose of 5 g/kg) for a 2 days on/off cycle from postnatal days 25-55. Either 2 (young adult) or 12-14 (middle-age) months post exposure, rats were tested on two spatial tasks: spontaneous alternation and novel object in place. Acetylcholine efflux was assessed in the hippocampus during both tasks. There was no adolescent ethanol-induced deficit on spontaneous alternation, but middle-aged male rats displayed lower alternation rates. Male rats exposed to ethanol during adolescence had blunted behavioral evoked acetylcholine during spontaneous alternation testing. All ethanol-exposed rats displayed suppression of the cholinergic neuronal phenotype. On the novel object in place task, regardless of sex, ethanol-exposed rats performed significantly worse than control-treated rats, and middle aged-rats, regardless of sex or ethanol exposure, were significantly impaired relative to young adult rats. These results indicate that male rats display earlier age-related cognitive impairment on a working memory task. Furthermore, male rats exposed to ethanol during adolescence have blunted behavior-evoked hippocampal acetylcholine efflux. In addition, middle-aged and ethanol-exposed rats, regardless of sex, are impaired at determining discrete spatial relationship between objects. This type of pattern separation impairment was associated with a loss of neurogenesis. Thus, binge-type adolescent ethanol exposure does affect the septohippocampal circuit, and can accelerate age-related cognitive impairment on select spatial tasks.

Sex differences in cholinergic circuits and behavioral disruptions following chronic ethanol exposure with and without thiamine deficiency.

BACKGROUND: Few studies have investigated differences in the vulnerabilities of males and females to alcohol use disorder and alcohol-related brain damage (ARBD). According to epidemiological and clinical findings, females appear to be more sensitive to the effects of alcohol and thiamine deficiency and have a worse prognosis in recovery from neurocognitive deficits compared with males. This study aimed to characterize the effects of chronic ethanol (EtOH) toxicity and thiamine deficiency across the sexes using rodent models. METHODS: Male and female Sprague Dawley rats were assigned to chronic forced EtOH treatment (CET), pyrithiamine-induced thiamine deficiency (PTD), combined CET-PTD, or pair-fed (PF) control treatment conditions. Following treatments, spatial working memory was assessed during a spontaneous alternation task while measuring acetylcholine (ACh) in the prefrontal cortex (PFC) and the hippocampus (HPC). The animals also underwent an operant-based attentional set-shifting task (ASST) for the analysis of behavioral flexibility. RESULTS: Female and male rats did not differ in terms of EtOH consumption; however, the CET and CET-PTD-treated female rats had lower BECs than male rats. Compared with the PF group, the CET, PTD, and CET-PTD groups exhibited spatial working memory impairments with corresponding reductions in ACh efflux in the PFC and HPC. The ASST revealed that CET-PTD-treated males and females displayed impairments marked by increased latency to make decisions. Thalamic shrinkage was prominent only in the CET-PTD and PTD treatment conditions, but no sex-specific effects were observed. CONCLUSIONS: Although the CET and CET-PTD-treated females had lower BECs than the males, they demonstrated similar cognitive impairments. These results provide evidence that female rats experience behavioral and neurochemical disruptions at lower levels of alcohol exposure than males and that chronic EtOH and thiamine deficiencies produce a unique behavioral profile.

Midline Thalamic Damage Associated with Alcohol-Use Disorders: Disruption of Distinct Thalamocortical Pathways and Function.

The thalamus, a significant part of the diencephalon, is a symmetrical and bilateral central brain structure. The thalamus is subdivided into three major groups of nuclei based on their function: sensorimotor nuclei (or principal/relay nuclei), limbic nuclei and nuclei bridging these two domains. Anatomically, nuclei within the thalamus are described by their location, such as anterior, medial, lateral, ventral, and posterior. In this review, we summarize the role of medial and midline thalamus in cognition, ranging from learning and memory to flexible adaptation. We focus on the discoveries in animal models of alcohol-related brain damage, which identify the loss of neurons in the medial and midline thalamus as drivers of cognitive dysfunction associated with alcohol use disorders. Models of developmental ethanol exposure and models of adult alcohol-related brain damage and are compared and contrasted, and it was revealed that there are similar (anterior thalamus) and different (intralaminar [adult exposure] versus ventral midline [developmental exposure]) thalamic pathology, as well as disruptions of thalamo-hippocampal and thalamo-cortical circuits. The final part of the review summarizes approaches to recover alcohol-related brain damage and cognitive and behavioral outcomes. These approaches include pharmacological, nutritional and behavioral interventions that demonstrated the potential to mitigate alcohol-related damage. In summary, the medial/midline thalamus is a significant contributor to cognition function, which is also sensitive to alcohol-related brain damage across the life span, and plays a role in alcohol-related cognitive dysfunction.

The Effect of Chronic Ethanol Exposure and Thiamine Deficiency on Myelin-related Genes in the Cortex and the Cerebellum.

BACKGROUND: Long-term alcohol consumption has been linked to structural and functional brain abnormalities. Furthermore, with persistent exposure to ethanol (EtOH), nutrient deficiencies often develop. Thiamine deficiency is a key contributor to alcohol-related brain damage and is suspected to contribute to white matter pathology. The expression of genes encoding myelin proteins in several cortical brain regions is altered with EtOH exposure. However, there is limited research regarding the impact of thiamine deficiency on myelin dysfunction. METHODS: A rat model was used to assess the impact of moderate chronic EtOH exposure (CET; 20% EtOH in drinking water for 1 or 6 months), pyrithiamine-induced thiamine deficiency treatment (PTD), both conditions combined (CET-PTD), or CET with thiamine injections (CET + T) on myelin-related gene expression (Olig1, Olig2, MBP, MAG, and MOG) in the frontal and parietal cortices and the cerebellum. RESULTS: The CET-PTD treatments caused the greatest suppression in myelin-related genes in the cortex. Specifically, the parietal cortex was the region that was most susceptible to PTD-CET-induced alterations in myelin-related genes. In addition, PTD treatment, with and without CET, caused minor fluctuations in the expression of several myelin-related genes in the frontal cortex. In contrast, CET alone and PTD alone suppressed several myelin-related genes in the cerebellum. Regardless of the region, there was significant recovery of myelin-related genes with extended abstinence and/or thiamine restoration. CONCLUSION: Moderate chronic EtOH alone had a minor effect on the suppression of myelin-related genes in the cortex; however, when combined with thiamine deficiency, the reduction was amplified. There was a suppression of myelin-related genes following long-term EtOH and thiamine deficiency in the cerebellum. However, the suppression in the myelin-related genes mostly occurred 24 h after EtOH removal or following thiamine restoration; within 3 weeks of abstinence or thiamine recovery, gene expression rebounded.

Preface: Setting the stage for understanding alcohol effects in late aging: A special issue including both human and rodent studies.

It is widely recognized that people worldwide are living longer than in previous decades, with formidable projections regarding the expansion of elderly age groups in the decades to come. Older individuals are also sustaining higher levels of alcohol consumption later in life, and binge drinking remains a prevalent pastime in a significant proportion of aged individuals. Older people are more sensitive to neurobehavioral effects of alcohol, and as individuals age, the cumulative impact of lifetime alcohol intake begins to emerge. This brief review provides a perspective on the emerging field of how alcohol interacts with the aging brain and sets the stage for understanding the relationship between alcohol and overall brain health. In doing so, we introduce a set of articles collected in this book series (all chapters available on PubMed) which spans human epidemiology and clinical outcomes, along with a series of neurobehavioral studies in preclinical (rodent) models. Because both natural aging as well as alcohol use and abuse include tell-tale signs of neuroinflammation (heightened expression of neuroimmune genes, activation of inflammatory signaling pathways, and signs of glial activation), particular emphasis is placed on the role of neuroinflammation in both aging- and alcohol-related alterations in neurobehavioral function, with special emphasis on the spectrum of cognitive dysfunction ranging from mild cognitive impairment to Alzheimer's associated brain pathology.

Aging with alcohol-related brain damage: Critical brain circuits associated with cognitive dysfunction.

Alcoholism is associated with brain damage and impaired cognitive functioning. The relative contributions of different etiological factors, such as alcohol, thiamine deficiency and age vulnerability, to the development of alcohol-related neuropathology and cognitive impairment are still poorly understood. One reason for this quandary is that both alcohol toxicity and thiamine deficiency produce brain damage and cognitive problems that can be modulated by age at exposure, aging following alcohol toxicity or thiamine deficiency, and aging during chronic alcohol exposure. Pre-clinical models of alcohol-related brain damage (ARBD) have elucidated some of the contributions of ethanol toxicity and thiamine deficiency to neuroinflammation, neuronal loss and functional deficits. However, the critical variable of age at the time of exposure or long-term aging with ARBD has been relatively ignored. Acute thiamine deficiency created a massive increase in neuroimmune genes and proteins within the thalamus and significant increases within the hippocampus and frontal cortex. Chronic ethanol treatment throughout adulthood produced very minor fluctuations in neuroimmune genes, regardless of brain region. Intermittent "binge-type" ethanol during the adolescent period established an intermediate neuroinflammatory response in the hippocampus and frontal cortex, that can persist into adulthood. Chronic excessive drinking throughout adulthood, adolescent intermittent ethanol exposure, and thiamine deficiency all led to a loss of the cholinergic neuronal phenotype within the basal forebrain, reduced hippocampal neurogenesis, and alterations in the frontal cortex. Only thiamine deficiency results in gross pathological lesions of the thalamus. The behavioral impairment following these types of treatments is hierarchical: Thiamine deficiency produces the greatest impairment of hippocampal- and prefrontal-dependent behaviors, chronic ethanol drinking ensues mild impairments on both types of tasks and adolescent intermittent ethanol exposure leads to impairments on frontocortical tasks, with sparing on most hippocampal-dependent tasks. However, our preliminary data suggest that as rodents age following adolescent intermittent ethanol exposure, hippocampal functional deficits began to emerge. A necessary requirement for the advancement of understanding the neural consequences of alcoholism is a more comprehensive assessment and understanding of how excessive alcohol drinking at different development periods (adolescence, early adulthood, middle-aged and aged) influences the trajectory of the aging process, including pathological aging and disease.

Nucleus reuniens of the midline thalamus of a rat is specifically damaged after early postnatal alcohol exposure.

Individuals diagnosed with fetal alcohol spectrum disorders often show behavioral impairments in executive functioning. Mechanistic studies have implicated coordination between the prefrontal cortex and the hippocampus (through thalamic nucleus reuniens) as essential for such executive functions. This study is the first to report the long-term neuroanatomical alterations to the ventral midline thalamus after alcohol exposure on postnatal days 4-9 (a rodent model of binge drinking during the third-trimester of human pregnancy). Alcohol added to a milk formula was administered to female Long-Evans rat pups on postnatal days 4-9 (5.25 g/kg/day of ethanol, intragastric intubation). Control animals were intubated without the administration of liquid. In adulthood, brains were immunohistochemically labeled for a neuronal marker (NeuN) conjugated with Cy3 fluorophore and stained with Hoechst33342 to visualize nuclei. Total non-neuronal cell number (NeuN/Hoechst) and neuron number (NeuN/Hoechst), and total volume were estimated using unbiased stereology in two neighboring midline thalamic nuclei: reuniens and rhomboid. Estimates were analyzed using linear mixed modeling to account for animal and litter as clustering variables. A 21% reduction in the total neuron number (resulting in altered neuron-to-non-neuron ratio) and an 18% reduction in total volume were found exclusively in thalamic nucleus reuniens in rats exposed to ethanol. Non-neuronal cell number was not changed in reuniens. No ethanol-induced changes on any measures were observed in rhomboid nucleus. These specific neuroanatomical alterations provide a necessary foundation for further examination of circuit-level alterations that occur in fetal alcohol spectrum disorder.

General anesthetic exposure in adolescent rats causes persistent maladaptations in cognitive and affective behaviors and neuroplasticity.

Accumulating evidence indicates that exposure to general anesthetics during infancy and childhood can cause persistent cognitive impairment, alterations in synaptic plasticity, and, to a lesser extent, increased incidence of behavioral disorders. Unfortunately, the developmental parameters of susceptibility to general anesthetics are not well understood. Adolescence is a critical developmental period wherein multiple late developing brain regions may also be vulnerable to enduring general anesthetic effects. Given the breadth of the adolescent age span, this group potentially represents millions more individuals than those exposed during early childhood. In this study, isoflurane exposure within a well-characterized adolescent period in Sprague-Dawley rats elicited immediate and persistent anxiety- and impulsive-like responding, as well as delayed cognitive impairment into adulthood. These behavioral abnormalities were paralleled by atypical dendritic spine morphology in the prefrontal cortex (PFC) and hippocampus (HPC), suggesting delayed anatomical maturation, and shifts in inhibitory function that suggest hypermaturation of extrasynaptic GABAA receptor inhibition. Preventing this hypermaturation of extrasynaptic GABAA receptor-mediated function in the PFC selectively reversed enhanced impulsivity resulting from adolescent isoflurane exposure. Taken together, these data demonstrate that the developmental window for susceptibility to enduring untoward effects of general anesthetics may be much longer than previously appreciated, and those effects may include affective behaviors in addition to cognition.

A Pivotal Role for Thiamine Deficiency in the Expression of Neuroinflammation Markers in Models of Alcohol-Related Brain Damage.

BACKGROUND: Alcohol-related brain damage (ARBD) is associated with neurotoxic effects of heavy alcohol use and nutritional deficiency, in particular thiamine deficiency (TD), both of which induce inflammatory responses in brain. Although neuroinflammation is a critical factor in the induction of ARBD, few studies have addressed the specific contribution(s) of ethanol (EtOH) versus TD. METHODS: Adult rats were randomly divided into 6 conditions: chronic EtOH treatment (CET) where rats consumed a 20% v/v solution of EtOH for 6 months; CET with injections of thiamine (CET + T); severe pyrithiamine-induced TD (PTD); moderate PTD; moderate PTD during CET; and pair-fed controls. After the treatments, the rats were split into 3 recovery phase time points: the last day of treatment (time point 1), acute recovery (time point 2: 24 hours posttreatment), and delayed recovery (time point 3: 3 weeks posttreatment). At these time points, vulnerable brain regions (thalamus, hippocampus, frontal cortex) were collected and changes in neuroimmune markers were assessed using a combination of reverse transcription polymerase chain reaction and protein analysis. RESULTS: CET led to minor fluctuations in neuroimmune genes, regardless of the structure being examined. In contrast, PTD treatment led to a profound increase in neuroimmune genes and proteins within the thalamus. Cytokine changes in the thalamus ranged in magnitude from moderate (3-fold and 4-fold increase in interleukin-1ß [IL-1ß] and IκBα) to severe (8-fold and 26-fold increase in tumor necrosis factor-α and IL-6, respectively). Though a similar pattern was observed in the hippocampus and frontal cortex, overall fold increases were moderate relative to the thalamus. Importantly, neuroimmune gene induction varied significantly as a function of severity of TD, and most genes displayed a gradual recovery across time. CONCLUSIONS: These data suggest an overt brain inflammatory response by TD and a subtle change by CET alone. Also, the prominent role of TD in the immune-related signaling pathways leads to unique regional and temporal profiles of induction of neuroimmune genes.

Nerve Growth Factor Is Responsible for Exercise-Induced Recovery of Septohippocampal Cholinergic Structure and Function.

Exercise has been shown to improve or rescue cognitive functioning in both humans and rodents, and the augmented actions of neurotrophins within the hippocampus and associated regions play a significant role in the improved neural plasticity. The septohippocampal circuit is modified by exercise. Beyond an enhancement of spatial working memory and a rescue of hippocampal activity-dependent acetylcholine (ACh) efflux, the re-emergence of the cholinergic/nestin neuronal phenotype within the medial septum/diagonal band (MS/dB) is observed following exercise (Hall and Savage, 2016). To determine which neurotrophin, brain-derived neurotrophic factor (BDNF) or nerve growth factor (NGF), is critical for exercise-induced cholinergic improvements, control and amnestic rats had either NGF or BDNF sequestered by TrkA-IgG or TrkB-IgG coated microbeads placed within the dorsal hippocampus. Hippocampal ACh release within the hippocampus during spontaneous alternation was measured and MS/dB cholinergic neuronal phenotypes were assessed. Sequestering NGF, but not BDNF, abolished the exercise-induced recovery of spatial working memory and ACh efflux. Furthermore, the re-emergence of the cholinergic/nestin neuronal phenotype within the MS/dB following exercise was also selectively dependent on the actions of NGF. Thus, exercise-induced enhancement of NGF within the septohippocampal pathway represents a key avenue for aiding failing septo-hippocampal functioning and therefore has significant potential for the recovery of memory and cognition in several neurological disorders.

Adolescent binge ethanol exposure alters specific forebrain cholinergic cell populations and leads to selective functional deficits in the prefrontal cortex.

Adolescence has been identified as a vulnerable developmental time period during which exposure to drugs can have long-lasting, detrimental effects. Although adolescent binge-like ethanol (EtOH) exposure leads to a significant reduction in forebrain cholinergic neurons, EtOH's functional effect on acetylcholine (ACh) release during behavior has yet to be examined. Using an adolescent intermittent ethanol exposure model (AIE), rats were exposed to binge-like levels of EtOH from postnatal days (PD) 25 to 55. Three weeks following the final EtOH exposure, cholinergic functioning was assessed during a spontaneous alternation protocol. During maze testing, ACh levels increased in both the hippocampus and prefrontal cortex. However, selectively in the prefrontal cortex, AIE rats displayed reduced levels of behaviorally relevant ACh efflux. We found no treatment differences in spatial exploration, spatial learning, spatial reversal, or novel object recognition. In contrast, AIE rats were impaired during the first attentional set shift on an operant set-shifting task, indicative of an EtOH-mediated deficit in cognitive flexibility. A unique pattern of cholinergic cell loss was observed in the basal forebrain following AIE: Within the medial septum/diagonal band there was a selective loss (30%) of choline acetyltransferase (ChAT)-positive neurons that were nestin negative (ChAT+/nestin-); whereas in the Nucleus basalis of Meynert (NbM) there was a selective reduction (50%) in ChAT+/nestin+. These results indicate that early adolescent binge EtOH exposure leads to a long-lasting frontocortical functional cholinergic deficit, driven by a loss of ChAT+/nestin+ neurons in the NbM, which was associated with impaired cognitive flexibility during adulthood.

Chronic intermittent ethanol exposure leads to alterations in brain-derived neurotrophic factor within the frontal cortex and impaired behavioral flexibility in both adolescent and adult rats.

Chronic intermittent exposure to ethanol (EtOH; CIE) that produces binge-like levels of intoxication has been associated with age-dependent deficits in cognitive functioning. Male Sprague-Dawley rats were exposed to CIE (5g/kg, 25% EtOH, 13 intragastric gavages) beginning at three ages: early adolescence (postnatal day [PD] 28), mid-adolescence (PD35) and adulthood (PD72). In experiment 1, rats were behaviorally tested following CIE. Spatial memory was not affected by CIE, but adult CIE rats were impaired at acquiring a non-spatial discrimination task and subsequent reversal tasks. Rats exposed to CIE during early or mid-adolescence were impaired on the first reversal, demonstrating transient impairment in behavioral flexibility. Blood EtOH concentrations negatively correlated with performance on reversal tasks. Experiment 2 examined changes in brain-derived neurotrophic factor (BDNF) levels within the frontal cortex (FC) and hippocampus (HPC) at four time points: during intoxication, 24 h after the final EtOH exposure (acute abstinence), 3 weeks following abstinence (recovery) and after behavioral testing. HPC BDNF levels were not affected by CIE at any time point. During intoxication, BDNF was suppressed in the FC, regardless of the age of exposure. However, during acute abstinence, reduced FC BDNF levels persisted in early adolescent CIE rats, whereas adult CIE rats displayed an increase in BDNF levels. Following recovery, neurotrophin levels in all CIE rats recovered. Our results indicate that intermittent binge-like EtOH exposure leads to acute disruptions in FC BDNF levels and long-lasting behavioral deficits. However, the type of cognitive impairment and its duration differ depending on the age of exposure.

BDNF regains function in hippocampal long-term potentiation deficits caused by diencephalic damage.

Thiamine deficiency (TD), commonly associated with chronic alcoholism, leads to diencephalic damage, hippocampal dysfunction, and spatial learning and memory deficits. We show a decrease in the magnitude of long-term potentiation (LTP) and paired-pulse facilitation (PPF) at CA3-CA1 synapses, independent of sex, following diencephalic damage induced by TD in rats. Thus, despite a lack of extensive hippocampal cell loss, diencephalic brain damage down-regulates plastic processes within the hippocampus, likely contributing to impaired hippocampal-dependent behaviors. However, both measures of hippocampal plasticity (LTP, PPF) were restored with brain-derived neurotrophic factor (BDNF), revealing an avenue for neural and behavioral recovery following diencephalic damage.

Chronic Drinking During Adolescence Predisposes the Adult Rat for Continued Heavy Drinking: Neurotrophin and Behavioral Adaptation after Long-Term, Continuous Ethanol Exposure.

Previous research has found that adolescent ethanol (EtOH) exposure alters drug seeking behaviors, cognition and neuroplasticity. Using male Sprague Dawley rats, differences in spatial working memory, non-spatial discrimination learning and behavioral flexibility were explored as a function of age at the onset (mid-adolescent vs. adult) of chronic EtOH exposure (CET). Concentrations of mature brain-derived neurotrophic factor (mBDNF) and beta-nerve growth factor (ß-NGF) in the prefrontal cortex and hippocampus were also assessed at different time-points: during CET, following acute abstinence (48-hrs), and after protracted abstinence (6-8 wks). Our results revealed that an adolescent onset of CET leads to increased EtOH consumption that persisted into adulthood. In both adult and adolescent onset CET groups, there were significant long-term reductions in prefrontal cortical mBDNF and ß-NGF levels. However, only adult onset CET rats displayed decreased hippocampal BDNF levels. Spatial memory, assessed by spontaneous alternation and delayed alternation, was not significantly affected by CET as a function of age of drinking onset, but higher blood-EtOH levels were correlated with lower spontaneous alternation scores. Regardless of the age of onset, EtOH exposed rats were impaired on non-spatial discrimination learning and displayed inflexible behavioral patterns upon reversal learning. Our results indicate that adolescent EtOH exposure changes long-term consumption patterns producing behavioral and neural dysfunctions that persist across the lifespan.

Exercise leads to the re-emergence of the cholinergic/nestin neuronal phenotype within the medial septum/diagonal band and subsequent rescue of both hippocampal ACh efflux and spatial behavior.

Exercise has been shown to improve cognitive functioning in a range of species, presumably through an increase in neurotrophins throughout the brain, but in particular the hippocampus. The current study assessed the ability of exercise to restore septohippocampal cholinergic functioning in the pyrithiamine-induced thiamine deficiency (PTD) rat model of the amnestic disorder Korsakoff Syndrome. After voluntary wheel running or sedentary control conditions (stationary wheel attached to the home cage), PTD and control rats were behaviorally tested with concurrent in vivo microdialysis, at one of two time points: 24-h or 2-weeks post-exercise. It was found that only after the 2-week adaption period did exercise lead to an interrelated sequence of events in PTD rats that included: (1) restored spatial working memory; (2) rescued behaviorally-stimulated hippocampal acetylcholine efflux; and (3) within the medial septum/diagonal band, the re-emergence of the cholinergic (choline acetyltransferase [ChAT+]) phenotype, with the greatest change occurring in the ChAT+/nestin+ neurons. Furthermore, in control rats, exercise followed by a 2-week adaption period improved hippocampal acetylcholine efflux and increased the number of neurons co-expressing the ChAT and nestin phenotype. These findings demonstrate a novel mechanism by which exercise can modulate the mature cholinergic/nestin neuronal phenotype leading to improved neurotransmitter function as well as enhanced learning and memory.

Interactions between chronic ethanol consumption and thiamine deficiency on neural plasticity, spatial memory, and cognitive flexibility.

BACKGROUND: Many alcoholics display moderate to severe cognitive dysfunction accompanied by brain pathology. A factor confounded with prolonged heavy alcohol consumption is poor nutrition, and many alcoholics are thiamine deficient. Thus, thiamine deficiency (TD) has emerged as a key factor underlying alcohol-related brain damage (ARBD). TD in humans can lead to Wernicke Encephalitis that can progress into Wernicke-Korsakoff syndrome and these disorders have a high prevalence among alcoholics. Animal models are critical for determining the exact contributions of ethanol (EtOH)- and TD-induced neurotoxicity, as well as the interactions of those factors to brain and cognitive dysfunction. METHODS: Adult rats were randomly assigned to 1 of 6 treatment conditions: chronic EtOH treatment (CET) where rats consumed a 20% v/v solution of EtOH over 6 months; severe pyrithiamine-induced TD (PTD-moderate acute stage); moderate PTD (PTD-early acute stage); moderate PTD followed by CET (PTD-CET); moderate PTD during CET (CET-PTD); and pair-fed (PF) control. After recovery from treatment, all rats were tested on spontaneous alternation and attentional set-shifting. After behavioral testing, brains were harvested for determination of mature brain-derived neurotrophic factor (BDNF) and thalamic pathology. RESULTS: Moderate TD combined with CET, regardless of treatment order, produced significant impairments in spatial memory, cognitive flexibility, and reductions in brain plasticity as measured by BDNF levels in the frontal cortex and hippocampus. These alterations are greater than those seen in moderate TD alone, and the synergistic effects of moderate TD with CET lead to a unique cognitive profile. However, CET did not exacerbate thalamic pathology seen after moderate TD. CONCLUSIONS: These data support the emerging theory that subclinical TD during chronic heavy alcohol consumption is critical for the development of significant cognitive impairment associated with ARBD.

Medial septum-diagonal band of Broca (MSDB) GABAergic regulation of hippocampal acetylcholine efflux is dependent on cognitive demands.

The septohippocampal pathway contains cholinergic, GABAergic, and glutamatergic projections and has an established role in learning, memory, and hippocampal theta rhythm. Both GABAergic and cholinergic neurons in the medial septum-diagonal band of Broca (MSDB) have been associated with spatial memory, but the relationship between the two neuronal populations is not fully understood. The present study investigated the effect of selective GABAergic MSDB lesions on hippocampal acetylcholine (ACh) efflux and spatial memory during tasks that varied in memory demand. Male Sprague Dawley rats were given GABAergic lesions of the MSDB using GAT1-saporin (GAT1-SAP) and examined on spontaneous exploration (Experiment 1) and non-matching to position without (NMTP; Experiment 2) and with a delay (DNMTP; Experiment 3), while concurrently using in vivo microdialysis to measure hippocampal ACh efflux. Intraseptal GAT1-SAP treatment did not alter baseline or behaviorally stimulated hippocampal ACh efflux or maze exploration (Experiment 1). Moreover, GAT1-SAP did not alter evoked hippocampal ACh efflux related to NMTP nor did it impair working memory in NMTP (Experiment 2). In contrast, both ACh efflux and performance in DNMTP were impaired by intraseptal GAT1-SAP. Thus, GABAergic MSDB neurons are important for spatial working memory and modulate hippocampal ACh efflux under conditions of high memory load. The relationship between the septohippocampal cholinergic and GABAergic systems and working memory will be discussed.

Thiamine deficiency degrades the link between spatial behavior and hippocampal synapsin I and phosphorylated synapsin I protein levels.

The links between spatial behavior and hippocampal levels of synapsin I and phosphosynapsin I were assessed in normal rats and in the pyrithiamine-induced thiamine deficiency (PTD) rat model of Wernicke-Korsakoff's syndrome. Synapsin I tethers small synaptic vesicles to the actin cytoskeleton in a phosphorylation-dependent manner, is involved in neurotransmitter release and has been implicated in hippocampal-dependent learning. Positive correlations between spontaneous alternation behavior and hippocampal levels of both synapsin I and phosphorylated synapsin I were found in control rats. However, spontaneous alternation performance was impaired in PTD rats and was accompanied by a significant reduction (30%) in phosphorylated synapsin I. Furthermore, no correlations were observed between either form of synapsin I and behavior in PTD rats. These data suggest that successful spontaneous alternation performance is related to high levels of hippocampal synapsin I and phosphorylated synapsin I. These results not only support the previous findings that implicate impaired hippocampal neurotransmission in the spatial learning and memory deficits associated with thiamine deficiency, but also suggest a presynaptic mechanism.