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.

Examination of cortically projecting cholinergic neurons following exercise and environmental intervention in a rodent model of fetal alcohol spectrum disorders.

BACKGROUND: Up to 1 in 5 infants in the United States are exposed to alcohol prenatally, resulting in neurodevelopmental deficits categorized as fetal alcohol spectrum disorders (FASD). Choline supplementation ameliorates some deficits, suggesting that alcohol exposure (AE) perturbs cholinergic neurotransmission and development. Behavioral interventions, which upregulate cholinergic neurotransmission, rescue cognitive deficits in rodent models of FASD. METHODS: We investigated the impacts of two interventions (either wheel-running (WR) or "super intervention," WR plus exposure to a complex environment) on cholinergic neuronal morphology in the nucleus basalis of Meynert (NBM), the source of cortical cholinergic input, and prefrontal cortex (PFC) in a rodent model of FASD. One third of the total 47 male pups received intragastric intubation of ethanol in milk substitute during postnatal days (PD) 4-9. Another third served as sham-intubated procedural controls while the final third served as suckle controls. Rats from each group were exposed to either intervention during PD 30-72. Choline acetyltransferase (ChAT+ ) and acetylcholinesterase staining were used to quantify cholinergic neuron number, soma volume, and axon number. RESULTS: Our data indicate a main effect of postnatal treatment on ChAT+ neuron number in NBM in adulthood. Post hoc analysis demonstrates that ChAT+ neuron number is reduced in AE compared to suckle control rodents (p < .01). CONCLUSIONS: We examined the cytoarchitectonics of cholinergic neurons in NBM and PFC in adulthood following early postnatal AE and two interventions. We show that AE reduces ChAT+ neuron number in NBM, and this is not mitigated by either intervention.

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.