Alcohol Consumption during Adolescence in a Mouse Model of Binge Drinking Alters the Intrinsic Excitability and Function of the Prefrontal Cortex through a Reduction in the Hyperpolarization-Activated Cation Current

Abstract

Periodic episodes of excessive alcohol consumption ("binge drinking") occur frequently among adolescents, and early binge drinking is associated with an increased risk of alcohol use disorders later in life. The PFC undergoes significant development during adolescence and hence may be especially susceptible to the effects of binge drinking. In humans and in animal models, adolescent alcohol exposure is known to alter PFC neuronal activity and produce deficits in PFC-dependent behaviors, such as decision making, response inhibition, and working memory. Using a voluntary intermittent access to alcohol (IA EtOH) procedure in male mice, we demonstrate that binge-level alcohol consumption during adolescence leads to altered drinking patterns and working memory deficits in young adulthood, two outcomes that suggest medial PFC dysfunction. We recorded from pyramidal neurons (PNs) in the prelimbic subregion of the medial PFC in slices obtained from mice that had IA EtOH and found that they display altered excitability, including a hyperpolarization of the resting membrane potential and reductions in the hyperpolarization-activated cation current (I) and in intrinsic persistent activity (a mode of neuronal firing that is dependent on I). Many of these effects on intrinsic excitability were sustained following abstinence and observed in mice that showed working memory deficits. In addition, we found that resting membrane potential and the I-dependent voltage "sag" in prelimbic PFC PNs are developmentally regulated during adolescence, suggesting that adolescent alcohol exposure may compromise PFC function by arresting the normal developmental trajectory of PN intrinsic excitability. Binge alcohol drinking during adolescence has negative consequences for the function of the developing PFC. Using a mouse model of voluntary binge drinking during adolescence, we found that this behavior leads to working memory deficits and altered drinking behavior in adulthood. In addition, we found that adolescent drinking is associated with specific changes to the intrinsic excitability of pyramidal neurons in the PFC, reducing the ability of these neurons to generate intrinsic persistent activity, a phenomenon thought to be important for working memory. These findings may help explain why human adolescent binge drinkers show performance deficits on tasks mediated by the PFC.

Estrogen Modulates Ethanol‐Induced Memory Deficit in Postpubertal Adolescent Rats

“…Postpubertal female rats subjected to acute EtOH treatment showed less freezing than vehicle‐treated female rats, but postpubertal EtOH‐treated male rats did not differ from vehicle‐treated male rat in their freezing behavior. Significant impairments in hippocampus‐associated spatial learning have been reported in both prepubertal male (Markwiese et al., ; Salling et al., ; Sircar and Sircar, ) and prepubertal female (Sircar et al., ) rats following repeated EtOH treatment, but not in adult rats (Markwiese et al., ; Sircar and Sircar, ; Sircar et al., ). Postpubertal male rats appear to behave adult‐like in terms of EtOH insensitivity on memory functions, whereas postpubertal female rats maintain EtOH‐induced memory impairment from the prepubertal period.…”

“…Vaginal opening, a sign of sexual maturation in rodents, occurs around PD35 (Sircar, ), and in male rodents, sexual maturation appears around PD40 (Varlinskaya et al., ). Although the effects of EtOH on memory functions have been extensively studied in prepubertal rats (Markwiese et al., ; Salling et al.,; Sircar and Sircar, ; Sircar et al., ), there is no study in the literature on effects of EtOH on cognitive functioning in postpubertal animals. Here, the effects of acute EtOH exposure on contextual fear conditioning, a hippocampus‐associated memory task, were examined in postpubertal adolescent male and female rats, and the role of the female gonadal hormone estrogen in EtOH's behavioral effects was investigated.…”

In Vivo Two-Photon Imaging of Neuronal and Vascular Responses in Mice Chronically Exposed to Ethanol

“…A wealth of studies using slice electrophysiology report that repeated exposures of rodents to alcohol induces changes in the excitability and synaptic properties of neurons in frontal cortex (Holmes et al, 2012;Kroener et al, 2012;Nimitvilai et al, 2016;Salling et al, 2018) and sub-cortical (Brodie, 2002;Hopf et al, 2007;Varodayan et al, 2017;Wang et al, 2007;Williams et al, 2018) areas. Fewer studies have examined the effects of ethanol on neuronal responses in visual or somatosensory cortices and these have largely focused on acute or neonatal exposures (reviewed by Medina and Krahe, 2008).…”

Constitutive Genetic Deletion of Hcn1 Increases Alcohol Preference during Adolescence

“…For example, they are important for establishing rhythmic firing in the thalamus and ventral tegmental area, while in the cortex they contribute to resting membrane potential, influence somatic and dendritic input resistance, and synaptic integration [24]. Intriguingly, in rodents, the HCN1 subunit channel undergoes developmental regulation during adolescence, which shows showing increased expression and function in pyramidal neurons in the hippocampus and prefrontal cortex as mice age from early adolescence to adulthood [21,25,26].…”