Specific Interests of the Laboratory:

The Effects of Nicotine on Learning and Memory

In 1988, the US Surgeon General concluded that tobacco products are addictive and that nicotine is the main pharmacological agent in tobacco responsible for tobacco's addictive nature. Many questions remain, however, about nicotine. It is not completely understood what nicotine's effects on neurological/behavioral function are nor is it understood why nicotine is addictive. One reason for the incomplete understanding of nicotine addiction may be that addiction is a complex disorder with many factors contributing to the disease. The symptoms of nicotine withdrawal, which can include physical symptoms, impairments in cognition, and mood dysfunction may be a critical factor in the high relapse rates that occur in cigarette smokers. Furthermore, genetic factors may modulate the acute, chronic, and withdrawal effects of nicotine on cognition. Although animal models have provided useful insight into the somatic and affective symptoms of nicotine withdrawal, little animal research has focused on the effects of nicotine withdrawal on learning. Research from our lab uses contextual fear conditioning, a hippocampus-dependent form of classical conditioning, as an animal model for the effects of nicotine on cognition. The goals of the NILA lab are: to investigate the effects of nicotine on learning, to identify the cellular and molecular mechanisms that are altered by nicotine use, and to identify genetic factors that may contribute to nicotine-associated neurobehavioral effects. The laboratory uses behavioral, pharmacological, genetic, molecular, and electrophysiological approaches to address these questions.



Therapeutics That Facilitate Smoking Cessation

Nicotine addiction is a disorder that may be maintained by many factors, including nicotine withdrawal-associated deficits in cognitive processes. One goal of our laboratory is to test pharmacological agents that can potentially reduce nicotine withdrawal-associated deficits in cognition. Previous research has established that the noradrenergic system is involved in both learning and attention, and recent studies from our lab have demonstrated that nicotine withdrawal-associated deficits in contextual fear conditioning can be reversed by both nicotine replacement and by norepinephrine reuptake inhibitors. By identifying cellular and molecular processes that can ameliorate the effects of nicotine, more effective smoking cessation strategies can be developed.

The Effects of Other Drugs of Abuse and Nicotine On Cognition

Alcohol is frequently referred to as a "gateway" substance to nicotine use and abuse, and research has demonstrated that nicotine use in adolescents can predict a transition from social to problem drinking. However, the reasons for why these two drugs are co-abused remain unclear, although several factors are likely to be involved. One possible explanation for the co-abuse of nicotine and alcohol is that nicotine may reduce some of the negative symptoms of alcohol, such as disrupted cognition. Evidence in favor of this explanation comes from studies that have shown that alcohol impairs learning in hippocampus-dependent and independent procedures, while nicotine can reverse these deficits. An additional goal of our laboratory is to examine the neural substrates underlying the interactive effects of alcohol and nicotine on learning, and also to understand the effects of alcohol on learning when administered alone. Understanding the interactive effects of these drugs on cognition will aid in developing more effective treatments for both alcoholism and nicotine addiction.

 

Techniques to Elucidating Learning and Memory:

The processes of learning, memory, cognition, and impulsivity can be evaluated through a variety of neurobiological techniques.

Behavioral Techiques

From a behavioral neuroscience viewpoint, learning and memory can be evaluated in rodents by measuring freezing to a context and cue previously paired with electric footshock, exploration of novel objects or objects in novel locations, or preference for a compartment of a chamber paired with drug.  Cognition and hierarchical processing can be assessed by measuring digging behavior of novel scent combinations.  Impulsivity can be measured by recording premature responding on an operant task.  The NILA lab seeks to use these behavioral techniques to evaluate the effects of acute, chronic, and withdrawal from chronic nicotine in various cognitive tasks.  Furthermore, by the use of direct infusions, we can determine the specific neural substrates involved in the effects of nicotine on behavior.

Brain slice showing placements of cannula in dorsal hippocampus and approximate spread of drug (methylene blue infusions)

CellularTechniques

Long-term potentiation (LTP) is an in vitro model for the cellular and molecular processes that may underlie learning and memory.  It has been demonstrated that nicotine can enhance hippocampal LTP, which is consistent with in vivo studies demonstrating that nicotine enhances hippocampus-dependent learning.  Thus, LTP is a useful model for understanding how nicotine can alter cognitive function.  Currently, the Gould lab is using genetically modified mice to determine the nicotinic acetylcholine receptors (nAChRs) that may be required for the effects of nicotine on hippocampal LTP.

Molecular Techniques

There are a number of molecular mechanisms that are known to underlie learning and memory and are altered by nicotine administration. Our lab examines changes in protein levels and protein activation via the use of western blots and immunohistochemistry (IHC) and we can examine interactions with the genome via chromatin immunoprecipitation (ChIP) and quantitative polymerase chain reaction (qPCR). Using these techniques we’ve probed the involvement of mitogen activated protein kinases (MAPKs) and various transcription factors in the effects of nicotine on learning and memory. Our goal is to determine the molecular mechanisms that underlie the various cognitive effects of nicotine administration.

Image of co-localization of DAPI stained nuclei and phosphorylated CREB in the prefrontal cortex of a mouse.

Western blot of phosphorylated ERK 1/2 in mice that were fear conditioned.

Other techniques

Pharmacological and genetic manipulations can be used to determine the contributions various receptor subtypes or protein kinases make to learning and memory processes, cognition, and impulsive behavior.  The goal of the Gould lab is to understand learning, memory, cognition, and impulsivity at various levels of analysis and to elucidate the role drugs of abuse play in modulating these processes.

Gel showing the genotypes of JNK1 knockout, heterozygous, and wildtype mice.