103 research outputs found
sj-docx-1-jop-10.1177_02698811231219058 – Supplemental material for Cilia loss on distinct neuron populations differentially alters cocaine-induced locomotion and reward
No full textSupplemental material, sj-docx-1-jop-10.1177_02698811231219058 for Cilia loss on distinct neuron populations differentially alters cocaine-induced locomotion and reward by Thomas Everett, Tyler W Ten Eyck, Chang-Hung Wu, Amanda L Shelowitz, Sofia M Stansbury, Alexandra Firek, Barry Setlow and Jeremy C McIntyre in Journal of Psychopharmacology</p
Establishing a rodent (Fischer 344 rat) model of mild cognitive impairment in aging
No full textMild Cognitive Impairment is characterized by age-related decline in a
variety of cognitive domains, including reference and working memory and
olfactory function. Importantly, declining age-related mnemonic abilities is not
inevitable; learning and memory deficits emerge in some people by middle-age
while others remain largely cognitively-intact even at advanced chronological
ages. The goal of this thesis is to establish a Fischer 344 (F344) rat model with
some features of human cognitive aging which can then be utilized to
undercover the neurobiological underpinnings of age-related cognitive deficits.
Young (6 mo), middle-aged (11 mo), and aged (22 mo) F344 rats were
behaviorally characterized in a well-established reference memory version of the
Morris water maze task. Indeed, age-related impairments did occur across the
lifespan. Moreover, the reference memory protocol used here was sufficiently
sensitive to detect a difference in individual abilities among aged F344 rats such
that approximately half of the rats performed on par with young while the other
half performed outside this range, demonstrating impairment. These data mimic
individual differences in declarative memory among aged humans. Subsequently, subsets of rats initially characterized on the reference memory
version of the water maze were tested on either a spatial working memory water
maze task or an olfactory discrimination task. Despite detecting an age-related
delay-dependent decline in spatial working memory, this impairment was not
correlated with spatial reference memory. In contrast, a strong and significant
relationship was observed among aged rats in the odor discrimination task such
that aged rats with the worst spatial reference memory were also the most
impaired in their ability to discriminate odors for a food reward. Importantly, this
subset of cognitively-impaired rats was not impaired on digging media
discrimination problems with identical task demands, nor were they anosmic.
These data are among the first to demonstrate a cross-domain cognitive
deficit in a rodent model of human aging. Together, the current study both
confirms the use of the naturalistic F344 rat model for the study of cognitive
deficits within the context of aging and provides the most comprehensive
cognitive profile of this rat population to date
AMPA-receptor mediated plasticity within the rat spinal cord
No full textPrevious research from our laboratory has demonstrated that the spinal cord is
capable of a simple form of instrumental learning. In this instrumental learning
paradigm, rats typically receive a complete spinal transection at the second thoracic
vertebra, and are tested 24 hours after surgery. Subjects that receive shock to a hind leg
quickly learn to maintain the leg in a flexed position, reducing net shock exposure
whenever that leg is extended (controllable shock). Subjects that receive shock that is
independent of leg position do not exhibit an increase in flexion duration (uncontrollable
shock). This behavioral deficit can be induced with shock to the leg or tail and as little
as 6 minutes of uncontrollable shock impairs learning for up to 48 hours.
The present thesis explores how the related ��-amino-3-hydroxy-5-methyl-4-
isoxazole propionic acid-receptor (AMPAR) ionotropic glutamate receptor affects spinal
instrumental learning. Experiment 1 showed that inactivation of the AMPAR by
administration of an antagonist blocks the acquisition of instrumental learning in a dose
dependant fashion. Experiment 2 demonstrated that blocking the AMPAR after the
acquisition of the instrumental response subsequently blocked the maintenance of that response. Experiment 3 revealed that antagonizing the AMPAR during uncontrollable
shock blocked the acquisition of the learning deficit. Experiments 4-6 demonstrated that
the activation of the AMPAR at high levels could acutely block the acquisition spinal
instrumental learning. Understanding how the AMPAR influences learning in the spinal
cord will lead us to develop therapeutic strategies for recovery of function after spinal
cord injury
The Roles of Nicotinic and Muscarinic Cholinergic Receptors in Risky and Impulsive Decision Making
No full textPsychopathological conditions in which decision making is impaired are
common and include schizophrenia, attention deficit hyperactivity disorder, and
addiction, among others. This dissertation aimed to investigate the role of cholinergic
signaling in risky and impulsive decision making. Rats were trained in either a
���probability discounting��� task in which they chose between small guaranteed and large
probabilistically delivered food rewards (a measure of risky decision making), or a
���delay discounting��� task in which they chose between small immediate and large
delayed food rewards (a measure of impulsive decision making). Rats were also divided
into high and low ���risk-taking��� or ���impulsive��� groups on the basis of their performance
in the tasks.
Experiments 1 and 2 examined the effects of cholinergic drugs on performance in
the probability and delay discounting task, respectively. In Experiment 1, acute
administration of the acetylcholinesterase inhibitor donepezil decreased choice of the
large risky reward in ���risk-taking��� rats. Acute administration of nicotine increased
choice of the large risky reward in both groups, whereas administration of the nicotinic receptor antagonist mecamylamine decreased choice of the large risky reward in ���risktaking���
rats. In Experiment 2, nicotine increased choice of the large delayed reward and
mecamylamine shifted impulsive choice in a non-specific manner in ���impulsive��� rats.
The muscarinic receptor agonist oxotremorine decreased choice of the large delayed
reward in ���non-impulsive��� rats and increased choice in ���impulsive��� rats, while treatment
with the muscarinic receptor antagonist atropine increased impulsive choice in all rats.
In Experiment 3, another group of rats was used to examine correlations between
baseline performance in both discounting tasks and nicotinic receptor density levels in
several brain regions. Impulsive choice was positively correlated with ��4��2 receptor
levels in ventral hippocampus and nucleus accumbens shell, and ��7 receptor levels in the
basolateral amygdala, such that greater impulsivity was associated with higher receptor
levels. Additionally, risky choice was negatively correlated with ��4��2 receptor levels in
nucleus accumbens shell, such that greater risk was associated with lower receptor
levels. These experiments suggest that cholinergic receptors are involved in cost-benefit
decision making and that they may prove a useful target for treatment of
psychopathological conditions in which decision-making deficits are present
The Role of Tumor Necrosis Factor-Alpha in Maladaptive Spinal Plasticity
No full textPrevious work has shown that the spinal cord is capable of supporting a simple
form of instrumental learning. Subjects that receive controllable shock to an extended
hind limb will increase the duration of limb flexion over time in order to reduce net
shock exposure. Exposure to as little as 6 minutes of uncontrollable stimulation prior to
instrumental testing can elicit a long-lasting learning deficit. Prior work has suggested
that this deficit may reflect an overexcitation of spinal neurons akin to central
sensitization, and that learning is inhibited by the saturation of plasticity. The
experiments in this dissertation were designed to test the role of the cytokine tumor
necrosis factor alpha (TNFa) in the induction and expression of the deficit. It is believed
that the inflammatory properties of TNFa may mediate the excitatory processes that lead
to maladaptive spinal functioning.
Experiments 1 and 2 tested the necessity of endogenous TNFa in the deficit
produced by uncontrollable shock. These experiments showed that the inhibition of
endogenous TNFa blocks both the induction and expression of the shock-induced
deficit, suggesting a necessary role for TNFa in mediating the inhibition of spinal
learning. Conversely, Experiment 3 was designed to test the sufficiency for TNFa in producing a learning deficit. I found that treatment with exogenous TNFa undermined
spinal learning in a dose-dependent fashion, whether given immediately, or 24 hours
prior to testing. Experiment 4 demonstrated that the long-term TNFa-induced deficit is
mediated by TNFa receptor activity, as a TNF inhibitor given prior to testing blocked
the expression of this deficit.
As TNFa has been shown to be predominantly of glial origin, I next assessed the
role that glia play in the TNFa-induced deficit. Experiment 5 showed that inhibiting
glial metabolism prior to TNFa treatment blocked the capacity for TNFa to produce a
long-term deficit. Experiment 6 assessed the potential for TNFa inhibition to block the
deficit induced by lipopolysaccharide (LPS), an agent known to induce TNFa. TNFa
has also been shown to drive neural excitation by increasing the trafficking of calciumpermeable
AMPA receptors to the active zone of the post-synaptic bouton. Experiment 7
showed that selectively antagonizing these receptors prior to testing blocked the TNFa-
induced deficit, suggesting a possible post-synaptic mechanism by which TNFa exerts
its effects.
Finally, histological evidence was sought to reinforce the previous behavioral
findings. Experiment 8 used quantitative RT-PCR to assess the differential expression of
TNFa mRNA in uncontrollably shocked subjects as compared to those receiving
controllable shock and no shock. To determine concentrations of TNFa protein, an
ELISA was run in Experiment 9 comparing uncontrollably shocked subjects to
unshocked controls
Methamphetamine self-administration in rats developmentally exposed to lead
No full textMethamphetamine is gaining mainstream popularity across the United States at
the same time that lead exposure remains at elevated levels. Perinatal
(gestation/lactation) lead exposure has been found to modify the reward efficacy of
various drugs of abuse (e.g., cocaine, opiates) across the phases of initial selection, use,
and abuse. Lead-induced changes in sensitivity to methamphetamine have not been
examined in animals perinatally exposed to lead. Accordingly, four studies were
conducted to examine the effects of perinatal lead exposure on adult self-administration
of intravenous (i.v.) methamphetamine across all relevant transition points of drug
addiction.
Adult female rats were administered a 16-mg lead or a control solution for
30 days prior to breeding with non-exposed males. Exposure continued through
pregnancy and lactation and was discontinued at weaning (postnatal day [PND] 21).
Animals born to control or lead-exposed dams received indwelling jugular catheters as
adults (PND 60 and PND 90) and subsequently were randomly assigned to one of the
four studies mentioned above, using only one male rat per litter for each study. In Experiment 1, an acquisition study revealed that perinatal exposure to
environmentally relevant levels of lead resulted in a smaller percentage of rats reaching
the criterion for intravenous (i.v.) methamphetamine (.02 mg/kg) acquisition, relative to
non-exposed controls. In Experiment 2, a dose-effect curve yielded a biphasic pattern of
attenuation of the self-administration of methamphetamine (.04 mg/kg) in lead-exposed
animals. In Experiment 3, lead-exposed animals reached lower breaking points for
methamphetamine (.04 mg/kg) in a progressive ratio task, in comparison to control
animals. Finally in Experiment 4, a reinstatement study revealed that perinatally leadexposed
animals showed a decreased propensity to relapse to methamphetamine (.04
mg/kg) self-administration after a period of forced abstinence. The general attenuation
to the rewarding efficacy of methamphetamine observed in animals perinatally exposed
to lead may functionally translate into a form of tolerance or counteradaptation. The
data collected from these four studies further strengthen the possibility that pollutants in
the environment may play a modulatory role in substance abuse
Faculty Opinions recommendation of Consequences of Adolescent Exposure to the Cannabinoid Receptor Agonist WIN55,212-2 on Working Memory in Female Rats.
No full textLocal Attentional Bias Increases Approach Motivation: Evidence from Event-Related Potentials and Frequency Analyses
No full textOver twenty years of research have examined the cognitive consequences of positive affect states, and suggested that positive affect leads to a broadening of cognition. However, this research has primarily examined positive affect that is low in approach motivational intensity (e.g. contentment). In my program of research, I have systematically examined positive affect that varies in approach motivational intensity, and found that positive affect high in approach motivation (e.g. desire) narrow cognition, whereas positive affect low in approach motivation broaden cognition. In this dissertation, I will review past models and present a motivational dimension model of affect that expands understanding of how affective states influence attentional and cognitive breadth. I then review a body of research that has varied the motivational intensity of positive and negative affect and found that affect of low motivational intensity broadens cognitive processes, whereas affect of high motivational intensity narrows cognitive processes. Furthermore, a bi-directional link exists between attentional narrowing and approach motivation, such that a narrowed attentional focus to appetitive stimuli causes greater approach motivation than a broadened attentional focus
Binge-eating behavior in mice: influences of restriction and palatability in a limited access model
No full textAnimal models of bingeing have typically used stress to induce bingeing. A
recent model, limited-access to high-fat diet (HFD), has shown that caloric restriction
and stress were not required to induce bingeing in rats. This study replicated this model
in mice, explored the fat content within the model, and investigated locomotor activation
associated with binge-eating. Adult mice were maintained on a restricted feeding (RF)
schedule of 2 h/d of access to chow or ad lib access to chow, and then provided limited
access to 45% HFD or 84% HFD for 30 min 3 d/ week for 6 total snack sessions.
Circadian activity was monitored for RF animals offered 84% HFD, and after 6 snack
sessions were complete, allowed continuous access to the 45% HFD or the 84% HFD for
two weeks to explore rebound feeding. Bingeing, defined by increasing intakes across
days, was reported for mice offered 45% HFD regardless of deprivation state (RF or ad
lib), while mice offered 84% HFD only exhibited bingeing when they were restricted.
Comparison of male and female mice maintained RF, offered 45% HFD snack, showed that females had higher intake (kcals/g-bw) while ad lib fed mice exhibited no sex
differences. Circadian recordings for female RF mice offered 84% HFD showed shifts in
activity from the first hour of dark cycle to the hour preceding the snack and supported
that offering the HFD produced alterations in food-associated arousal. During rebound,
female RF mice given 84% HFD showed the highest intakes in week 1, and then
exhibited a marked decline in week 2. The week 1 intake for RF animals were to regain
lost body weight and that homeostatic-like intake in week 2 allowed normal body weight
maintenance.
Results of this investigation support human data that females are more
susceptible to binge-type eating disorder, shows that limited access to palatable foods for
females under caloric restriction induces changes in circadian activity, and reveals that
using mice in this model requires more investigation to optimize binge-behavior. Diet
comparisons also suggest that homeostatic and reward mechanisms may have an additive
effect on bingeing
Multiple memory systems and extinction: the neurobiological basis of latent extinction
No full textUnderstanding the neural mechanisms underlying the extinction of maladaptive
behaviors has become increasingly relevant. Extinction, or the reduction of a response
due to lack of reinforcement, is believed to be ���new learning.��� Most extinction paradigms
involve the performance of the previously reinforced response in the absence of
reinforcement in order for extinction to occur. Conversely, latent extinction is a cognitive
form of learning in which the previously rewarded response is not made during extinction
training. However, until now the neurobiological basis of latent extinction has remained
unknown.
This dissertation has three aims to examine the neurobiological basis of latent
extinction. Previous research has shown latent extinction to be impaired following
hippocampal inactivation and the goal of Aim 1 was to examine other neural systems
potentially involved in latent extinction through examination of brain structures such as
the dorsal striatum, medial prefrontal cortex, and basolateral amygdala. Additionally, the
neurochemical basis of latent extinction is unidentified; therefore Aim 2 addressed this
question, specifically investigating the glutamatergic system through both NMDA receptor agonism and antagonism. Finally, understanding latent extinction may be useful
for the extinction of drug addiction. Aim 3 was to examine some clinical implications for
the extinction of drug addiction utilizing latent extinction following maze running for an
oral cocaine reward.
Reversible neural inactivation studies using the sodium channel blocker
bupivacaine demonstrated a selective impairment of response extinction following dorsal
striatum inactivation, but no effect on either latent or response extinction following
medial prefrontal cortex or basolateral amygdala inactivation. These results, coupled with
previous data from our lab demonstrate a double dissociation for extinction behavior.
Further, peripheral NMDA receptor agonism with D-cyloserine enhances latent
extinction and intra-hippocampal NMDA receptor antagonism with AP5 impairs latent
extinction, identifying a role for the glutamatergic system in latent extinction. Finally,
oral cocaine administration during acquisition selectively impairs latent extinction
indicating that drug use affects the relive use of multiple memory systems during
extinction. Overall, the multiple memory systems theory and latent extinction provide a
framework with which to further understand the neural mechanisms of extinction
behavior
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