Impulsivity in rodents with a genetic predisposition for excessive alcohol consumption is associated with a lack of a prospective strategy

Increasing evidence supports the hypothesis that impulsive decision-making is a heritable risk factor for an alcohol use disorder (AUD). Clearly identifying a link between impulsivity and AUD risk, however, is complicated by the fact that both AUDs and impulsivity are heterogeneous constructs. Understanding the link between the two requires identifying the underlying cognitive factors that lead to impulsive choices. Rodent models have established that a family history of excessive drinking can lead to the expression of a transgenerational impulsive phenotype, suggesting heritable alterations in the decision-making process. In the present study, we explored the cognitive processes underlying impulsive choice in a validated, selectively bred rodent model of excessive drinking-the alcohol-preferring ("P") rat. Impulsivity was measured via delay discounting (DD), and P rats exhibited an impulsive phenotype as compared to their outbred foundation strain-Wistar rats. Steeper discounting in P rats was associated with a lack of a prospective behavioral strategy, which was observed in Wistar rats and was directly related to DD. To further explore the underlying cognitive factors mediating these observations, a drift diffusion model of DD was constructed. These simulations supported the hypothesis that prospective memory of the delayed reward guided choice decisions, slowed discounting, and optimized the fit of the model to the experimental data. Collectively, these data suggest that a deficit in forming or maintaining a prospective behavioral plan is a critical intermediary to delaying reward, and by extension, may underlie the inability to delay reward in those with increased AUD risk

Self-administration of edible Δ9-tetrahydrocannabinol and associated behavioral effects in mice

Background With increasing access to legal cannabis across the globe, it is imperative to more closely study its behavioral and physiological effects. Furthermore, with the proliferation of cannabis use, modes of consumption are changing, with edible formulations becoming increasingly popular. Nevertheless, there are relatively few animal models of self-administration of the primary psychoactive component of cannabis, Δ9-tetrahydrocannabinol (THC), and almost all incorporate routes of administration other than those used by humans. The aim of the current study was to develop a model of edible THC self-administration and assess its impact on CB1 receptor-mediated behaviors in female and male mice. Methods Mice were given limited access to a palatable dough which occasionally contained THC in doses ranging from 1 to 10 mg/kg. Following dough consumption, mice were assessed for home cage locomotor activity, body temperature, or analgesia. Locomotor activity was also assessed in conjunction with the CB1 receptor antagonist SR141716A. Results Dough was well-consumed, but consumption decreased at the highest THC concentrations. Edible THC produced dose-dependent decreases in locomotor activity and body temperature in both sexes, and these effects were more pronounced in male mice. Hypolocomotion induced by edible THC was attenuated by SR141716A, indicating mediation by CB1 receptor activation. Conclusions In contrast to other cannabinoid self-administration models, edible THC is relatively low in stress and uses a route of administration analogous to one used by humans. Potential applications include chronic THC self-administration, determining THC reward/reinforcement, and investigating consequences of oral THC use

Neural firing in the prefrontal cortex during alcohol intake in alcohol preferring ‘P’ vs. Wistar rats

BACKGROUND: Neural activity within the prefrontal cortex (PFC) is altered by alcohol and alcohol-associated stimuli and is mediated by genetic susceptibility to alcoholism. However, very little is known about how genetic risk of excessive drinking might mediate neural firing in the PFC during alcohol consumption. METHODS: To determine how genetic risk influences alcohol seeking, intake, and neural activity, a Pavlovian alcohol consumption task was used-the 2-Way Cued Access Protocol (2CAP). Alcohol-preferring "P" rats and relatives of their (heterogeneous) founding Wistar population were used for these studies. After acquisition of 2CAP, extinction of responding for alcohol was evaluated by substituting water for alcohol. Following these experiments, in vivo electrophysiological recordings were obtained during 2CAP from the PFC in a separate cohort of Wistar and P rats implanted with moveable tetrode microdrives. RESULTS: P and Wistar rats increased daily alcohol seeking and intake with P rats consuming roughly twice as much alcohol as Wistar. Both rat populations decreased seeking behavior during extinction. However, P rats displayed persistent increases in seeking after controlling for intake versus Wistar. Higher firing rates (FRs) were observed in P rats prior to 2CAP and throughout alcohol and water consumption compared with Wistars that were matched for alcohol-drinking history. Differences in FR were driven, in part, by a larger percentage of neurons in P rats versus Wistars that increased FR compared with those that decreased, or did not change. CONCLUSIONS: These data provide additional evidence of increased alcohol consumption and persistent alcohol seeking in P versus Wistar rats. Differences in PFC neural firing observed in P rats prior to drinking could be heritable and/or related to an enhanced response to alcohol-associated contextual cues. FR differences observed during alcohol drinking might be related to an augmented sensitivity of PFC neurons to orally consumed alcohol

A Tutorial for Information Theory in Neuroscience

Understanding how neural systems integrate, encode, and compute information is central to understanding brain function. Frequently, data from neuroscience experiments are multivariate, the interactions between the variables are nonlinear, and the landscape of hypothesized or possible interactions between variables is extremely broad. Information theory is well suited to address these types of data, as it possesses multivariate analysis tools, it can be applied to many different types of data, it can capture nonlinear interactions, and it does not require assumptions about the structure of the underlying data (i.e., it is model independent). In this article, we walk through the mathematics of information theory along with common logistical problems associated with data type, data binning, data quantity requirements, bias, and significance testing. Next, we analyze models inspired by canonical neuroscience experiments to improve understanding and demonstrate the strengths of information theory analyses. To facilitate the use of information theory analyses, and an understanding of how these analyses are implemented, we also provide a free MATLAB software package that can be applied to a wide range of data from neuroscience experiments, as well as from other fields of study

Acute d-Amphetamine alters the temporal patterning of intermittent synchronized oscillations in hippocampal and prefrontal circuits of the rat

poster abstractD-Amphetamine (d-AMPH) increases the bioavailability of numerous catecholamines, including dopamine, throughout the brain and modulates neural firing in cortical and subcortical regions. While a complex array of d-AMPH-mediated effects on firing have been reported, less is known regarding how d-AMPH affects the oscillatory properties of cortical circuits. In the current study, we simultaneously recorded local field potentials from electrode arrays implanted in the medial prefrontal cortex (PFC) and hippocampus (HC) of awake freely moving rats treated with saline, 1.0 mg/kg, or 3.3 mg/kg d-AMPH. The fine temporal structure of synchrony in delta, theta, beta, and gamma bands between these brain regions was examined to characterize how phase synchronization was altered by each dose of d-AMPH relative to saline. Differences were observed in the average level of phase-locking and in the variation of temporal patterns of synchrony on short (sub-second) time scales (including the distribution of durations of desynchronization events. In general, treatment with d-AMPH evoked higher levels of phase-locking. While this imperfect phase-locking can be potentially attained with both large number of short desynchronization episodes and small number of long desynchronization episodes, the data are marked by the dominance of short desynchronization episodes. These results suggest that within the HC and PFC, d-AMPH acts to increase synchronized oscillatory activity. The dominance of short desynchronization episodes suggests that the synchrony can be easily destabilized, yet it can be quickly re-established. The ease with which neural circuits can transition between synchronized and desynchronized dynamics may reflect altered information transfer regimes in these circuits and contribute to the spectrum of effects on cognition frequently observed with d-AMPH

IS COGNITIVE FUNCTION IMPAIRED IN A RODENT MODEL OF ALCOHOLISM?

poster abstractAlcohol abuse is a major problem in society resulting in issues of health, family, and economics. The relationship between an individual’s genetic makeup and their environment is becoming a primary focus of preclinical and clinical research that seeks to understand the etiology of alcoholism. Ex-cessive drinking may be the result of the inability of advanced forms of cog-nition to properly govern behavior, and the current proposal explored this possibility. This study used Wistar and alcohol preferring rats (P-rats) to in-vestigate the relationship between the phenotypic vulnerability for alcohol-ism and its relationship to cognitive functions. Rats were given four weeks of intermittent alcohol access and completed a cognitively demanding task known as operant set-shifting. The effects of prior alcohol exposure in vul-nerable versus non-vulnerable phenotypes was examined. Thus far no dif-ferences between lines have been observed in the ability to learn a new task that gauges function of the prefrontal cortex. These data are inconclusive and require further analysis, but may indicate that the cognitive task is not demanding enough to show differences in prefrontal cortex functioning. Re-sults from the drinking study confirmed that alcohol drinking significantly in-creased over the four weeks of testing for P-rats, but not Wistars. P-rats also significantly increased ethanol consumption measured during the first 30 minutes of access throughout the drinking protocol. Results from this study show how future tests could improve our current understanding of the rela-tionship between alcohol abuse and cognition and can help guide future re-search to better understand this disease. School of Science Start-up funds and RSFG to C. Lapish. UROP to B. Tod

Dynamics of synchronized neural activity in prefrontal-hippocampal networks during behavioral sensitization

poster abstractNeural synchrony exhibits temporal variability, therefore the temporal patterns of synchronization and desynchronization may have functional relevance. This study employs novel time-series analysis to explore how neural signals become transiently phase locked and unlocked during repeated injections of the psychostimulant, D-Amphetamine (AMPH). Short (but frequent) desynchronized events dominate synchronized dynamics in each of the animals we examined. After the first AMPH injection, only increases in the relative prevalence of short desynchronization episodes (but not in average synchrony strength) were significant. Throughout sensitization both strength and the fine temporal structure of synchrony (measured as relative prevalence of short desynchronizations) were similarly altered with AMPH injections, with each measure decreasing in the pre-injection epoch and increasing after injection. Decoupling between locomotor activity and synchrony was observed in AMPH, but not saline, animals. The increase in numerous short desynchronizations (as opposed to infrequent, but long desynchronizations) in AMPH treated animals may indicate that synchrony is easy to form yet easy to break. These data yield novel insight into how synchrony is dynamically altered in cortical networks by AMPH and identify neurophysiological changes that may be important to understand the behavioral pathologies of addiction