Biomedical subjects

Barry Setlow

Publications and source records attributed to Barry Setlow.

16 recordsLinked to original sources

PubMed2025

Contribution of the Brain-Gut-Microbiome Axis to Intergenerational Abnormalities in a Rat Model of Perioperative Neurocognitive Disorder.

BACKGROUND: The brain-gut-microbiome (BGM) axis is a communication network through which the brain and gastrointestinal microbiota interact via neural, hormonal, immune, and gene expression mechanisms. Gut microbiota dysbiosis is thought to contribute to neurocognitive disorders, including perioperative neurocognitive disorder, and to various metabolic abnormalities. Recently, the authors reported that sevoflurane induces neurocognitive deficits in exposed rats as well as their future offspring, with male offspring being particularly affected (intergenerational perioperative neurocognitive disorder). In this study, the authors examined in the same animals whether the intergenerational effects of sevoflurane involve abnormalities in the BGM axis, and whether they are mitigated by paternal pretreatment with either the Na + -K + -Cl - (NKCC1) Cl - transporter inhibitor bumetanide or the glucocorticoid receptor inhibitor RU486, as previously demonstrated for neurocognitive deficits. METHODS: Male Sprague-Dawley rats (F0 generation) were exposed to 2.1% sevoflurane for 3 h on postnatal days 56, 58, and 60 (F0M_S group). Before each sevoflurane exposure, distinct experimental groups of F0 males received bumetanide (F0M_BS group) or RU486 (F0M_RS group). These males were mated on postnatal day 90 to produce offspring (F1 generation). Gut microbiota were profiled using 16S rRNA gene sequencing, and brain changes analyzed via RNA sequencing of hippocampal samples. RESULTS: F1 male offspring of F0M_S sires exhibited heightened corticosterone responses to stress, increased inflammatory markers, altered hippocampal transcriptomes, gut microbiota dysbiosis, elevated serum low-density lipoprotein cholesterol levels, and increased body weight. The only abnormality observed in F1 females was a shift in microbial diversity. F0M_S displayed profound alterations in hippocampal transcriptome, while microbial diversity was the only parameter affected in their gut microbiota. Bumetanide or RU486 mitigated most abnormalities, except increased body weight in F1 males. CONCLUSIONS: Paternal sevoflurane exposure in rats induces BGM axis abnormalities, particularly in male offspring, despite the absence of direct anesthetic exposure. Pretreatment with bumetanide or RU486 showed therapeutic efficacy.

Animals↗

PubMed2006

Deficits across multiple cognitive domains in a subset of aged Fischer 344 rats.

Rodent models of cognitive aging routinely use spatial performance on the water maze to characterize medial temporal lobe integrity. Water maze performance is dependent upon this system and, as in the aged human population, individual differences in learning abilities are reliably observed among spatially characterized aged rats. However, unlike human aging in which cognitive deficits rarely occur in isolation, few non-spatial learning deficits have been identified in association with spatial impairment among aged rats. In this study, a subset of male aged Fischer 344 rats was impaired both in water maze and odor discrimination tasks, whereas other aged cohorts performed on par with young adult rats in both settings. The odor discrimination learning deficits were reliable across multiple problems. Moreover, these deficits were not a consequence of anosmia and were specific to olfactory learning, as cognitively impaired aged rats performed normally on an analogous non-olfactory discrimination task. These are among the first data to describe an aging model in which individual variability among aged rat cognition occurs across two independent behavioral domains.

Aging↗

PubMed2006

Post-training amphetamine administration enhances memory consolidation in appetitive Pavlovian conditioning: Implications for drug addiction.

It has been suggested that some of the addictive potential of psychostimulant drugs of abuse such as amphetamine may result from their ability to enhance memory for drug-related experiences through actions on memory consolidation. This experiment examined whether amphetamine can specifically enhance consolidation of memory for a Pavlovian association between a neutral conditioned stimulus (CS-a light) and a rewarding unconditioned stimulus (US-food), as Pavlovian conditioning of this sort plays a major role in drug addiction. Male Long-Evans rats were given six training sessions consisting of 8 CS presentations followed by delivery of the food into a recessed food cup. After the 1st, 3rd, and 5th session, rats received subcutaneous injections of amphetamine (1.0 or 2.0 mg/kg) or saline vehicle immediately following training. Conditioned responding was assessed using the percentage of time rats spent in the food cup during the CS relative to a pre-CS baseline period. Both amphetamine-treated groups showed significantly more selective conditioned responding than saline controls. In a control experiment, there were no differences among groups given saline, 1.0 or 2.0 mg/kg amphetamine 2 h post-training, suggesting that immediate post-training amphetamine enhanced performance specifically through actions on memory consolidation rather than through non-mnemonic processes. This procedure modeled Pavlovian learning involved in drug addiction, in which the emotional valence of a drug reward is transferred to neutral drug-predictive stimuli such as drug paraphernalia. These data suggest that amphetamine may contribute to its addictive potential through actions specifically on memory consolidation.

Amphetamine↗

PubMed2005

Encoding changes in orbitofrontal cortex in reversal-impaired aged rats.

Previous work in rats and primates has shown that normal aging can be associated with a decline in cognitive flexibility mediated by prefrontal circuits. For example, aged rats are impaired in rapid reversal learning, which in young rats depends critically on the orbitofrontal cortex. To assess whether aging-related reversal impairments reflect orbitofrontal dysfunction, we identified aged rats with reversal learning deficits and then recorded single units as these rats, along with unimpaired aged cohorts and young control rats, learned and reversed a series of odor discrimination problems. We found that the flexibility of neural correlates in orbitofrontal cortex was markedly diminished in aged rats characterized as reversal-impaired in initial training. In particular, although many cue-selective neurons in young and aged-unimpaired rats reversed odor preference when the odor-outcome associations were reversed, cue-selective neurons in reversal-impaired aged rats did not. In addition, outcome-expectant neurons in aged-impaired rats failed to become active during cue sampling after learning. These altered features of neural encoding could provide a basis for cognitive inflexibility associated with normal aging.

Action Potentials↗

PubMed2005

Memory-influencing intra-basolateral amygdala drug infusions modulate expression of Arc protein in the hippocampus.

Activation of beta-adrenoceptors in the basolateral complex of the amygdala (BLA) modulates memory storage processes and long-term potentiation in downstream targets of BLA efferents, including the hippocampus. Here, we show that this activation also increases hippocampal levels of activity-regulated cytoskeletal protein (Arc), an immediate-early gene (also termed Arg 3.1) implicated in hippocampal synaptic plasticity and memory consolidation processes. Infusions of the beta-adrenoreceptor agonist, clenbuterol, into the BLA immediately after training on an inhibitory avoidance task enhanced memory tested 48 h later. The same dose of clenbuterol significantly increased Arc protein levels in the dorsal hippocampus. Additionally, posttraining intra-BLA infusions of a memory-impairing dose of lidocaine significantly reduced Arc protein levels in the dorsal hippocampus. Increases in Arc protein levels were not accompanied by increases in Arc mRNA, suggesting that amygdala modulation of Arc protein and synaptic plasticity in efferent brain regions occurs at a posttranscriptional level. Finally, infusions of Arc antisense oligodeoxynucleotides into the dorsal hippocampus impaired performance of an inhibitory avoidance task, indicating that the changes in Arc protein expression are related to the observed changes in memory performance.

Adrenergic beta-Agonists↗

PubMed2004

Cocaine makes actions insensitive to outcomes but not extinction: implications for altered orbitofrontal-amygdalar function.

Addiction is characterized by persistent drug-seeking despite adverse consequences or outcomes. Such persistent behavior may result from drug-induced brain changes that increase the control of behavior by associations between antecedent cues and responses. However, it is equally plausible that brain changes cause a decrease in the control of behavior by the value of likely outcomes. To test whether drug exposure can cause persistent behavior, and to distinguish between these two accounts of such behavior, we tested cocaine-experienced rats in a Pavlovian 'reinforcer devaluation' task, which provides independent assessments of the control of behavior by antecedent cues and outcome representations. We found that cocaine exposure caused persistent responding in this setting a month after the last drug treatment, and that this deficit resulted from an inability to use representations of outcome value to guide behavior rather than from changes in stimulus-response learning or response inhibition.

Amygdala↗

PubMed2004

Cocaine-experienced rats exhibit learning deficits in a task sensitive to orbitofrontal cortex lesions.

Addictive drugs, such as cocaine, cause long-lasting neural changes in prefrontal cortex. It has been hypothesized that these changes affect the behavioural control mediated by orbitofrontal cortex. To test this hypothesis, rats were given injections of cocaine (30 mg/kg/d, i.p.) or vehicle for 14 days and then trained after a 2-week withdrawal period in an odor discrimination task sensitive to the effects of orbitofrontal cortex lesions. We found that cocaine-treated rats, who demonstrated long-lasting sensitization to the locomotor activating effects of cocaine, failed to show normal changes in response latency during discrimination learning and were also slower than controls to acquire serial reversals. These behavioural impairments are identical to the effects of orbitofrontal cortex lesions in this task and show that cocaine exposure in rats can cause long-lasting effects on orbitofrontal-dependent functions. Notably, these effects were not correlated with increases in locomotor activity linked to cocaine-induced psychomotor sensitization observed before or after training, suggesting that the brain changes underlying the behavioural effects in the discrimination task are different from those mediating psychomotor sensitization.

Anesthetics, Local↗

PubMed2003

Different roles for orbitofrontal cortex and basolateral amygdala in a reinforcer devaluation task.

The orbitofrontal cortex (OFC) and basolateral amygdala (BLA) are critical for using learned representations of outcomes to guide behavior. Neurophysiological findings suggest complementary roles in which the BLA acquires associations between cues and outcomes and the OFC subsequently uses them to guide behavior. Here, we have used a reinforcer devaluation paradigm to test this hypothesis. In this paradigm, rats are first trained to associate a light conditioned stimulus (CS) with a food outcome, and then the food is devalued by pairing it with illness. After this devaluation procedure, responding to the CS is assessed in a single probe session. Previously, we have shown that BLA and OFC lesions made before training do not affect the acquisition of conditioned responding but do impair the sensitivity of that responding to reinforcer devaluation. Rats with such lesions fail to exhibit the spontaneous decrease in conditioned responding to the light cue observed in controls in the probe test. Here, we have extended those findings by showing that performance in the probe test is impaired by OFC lesions made after light-food conditioning but not by BLA lesions made after that training. These findings indicate that the OFC and BLA play different roles in mediating normal goal-directed performance in this, and likely other, settings. The BLA seems critical to forming representations linking cues to the incentive properties of outcomes but not for maintaining these representations in memory, updating them with new information, or for expressing them in behavior. In contrast, the OFC seems essential for one or more of these latter processes.

Amygdala↗

PubMed2003

A systems approach to orbitofrontal cortex function: recordings in rat orbitofrontal cortex reveal interactions with different learning systems.

The recognition that certain aspects of prefrontal function can be effectively modeled in rats has led to a slow expansion of interest in rat prefrontal cortex over the past decade. One of the most promising of these model systems is the orbitofrontal cortex of the rat. Rat orbitofrontal cortex is anatomically similar to the orbital prefrontal region in primates, and this similarity is borne out by behavioral and neurophysiological findings. Here we will present data on orbitofrontal cortex function from a number of parallel studies from our laboratories that employed single unit recording techniques to probe neural encoding in rat orbitofrontal cortex and related parts of the amygdala and the hippocampal memory systems. Together, these reports and associated behavioral studies suggest that the orbitofrontal region, in both rats and primates, is specialized to integrate concrete and abstract sensory constructs with information regarding the incentive value of associated outcomes to guide or modulate behavior. To the extent that monkey prefrontal function can model certain aspects of human prefrontal function, we argue that this model can now be extended to the rat orbitofrontal cortex. In addition, we argue that the function of orbitofrontal cortex needs to be considered in terms of its interactions with other brain systems.

Action Potentials↗

PubMed2003

Lesions of nucleus accumbens disrupt learning about aversive outcomes.

Nucleus accumbens (NAcc) is critical for encoding and using information regarding the learned significance of cues predictive of reward. However, its role in processing information about cues predictive of aversive outcomes is less well studied. Here, we examined the effects of NAcc lesions in an odor-guided discrimination task in which rats use odor cues predictive of either appetitive or aversive outcomes to guide responding. Rats with sham or neurotoxic lesions of NAcc were trained on a series of two-odor discrimination problems. Performance on each problem was assessed by monitoring accuracy of choice behavior and by measuring latency to respond for fluid reinforcement after odor sampling. After acquisition of four problems, rats were trained on serial reversals of the final problem. Rats with NAcc lesions exhibited normal choice performance relative to controls on both acquisition and reversal of the discrimination problems (indeed, lesioned rats exhibited a mild facilitation on the first discrimination problem). Despite normal choice performance, however, lesioned rats failed to show normal changes in response latency during discrimination learning, particularly on trials involving the aversive outcome. These findings are consistent with a deficit in processing cue-outcome associations. These results are compared with those obtained from studies of basolateral amygdala and orbitofrontal cortex lesions in this task and suggest that NAcc integrates the motivational value of both appetitive and aversive cues to bias or modulate the vigor of subsequent responding.

Animals↗

PubMed2003

Encoding predicted outcome and acquired value in orbitofrontal cortex during cue sampling depends upon input from basolateral amygdala.

Certain goal-directed behaviors depend critically upon interactions between orbitofrontal cortex (OFC) and basolateral amygdala (ABL). Here we describe direct neurophysiological evidence of this cooperative function. We recorded from OFC in intact and ABL-lesioned rats learning odor discrimination problems. As rats learned these problems, we found that lesioned rats exhibited marked changes in the information represented in OFC during odor cue sampling. Lesioned rats had fewer cue-selective neurons in OFC after learning; the cue-selective population in lesioned rats did not include neurons that were also responsive in anticipation of the predicted outcome; and the cue-activated representations that remained in lesioned rats were less associative and more often bound to cue identity. The results provide a neural substrate for representing acquired value and features of the predicted outcome during cue sampling, disruption of which could account for deficits in goal-directed behavior after damage to this system.

Amygdala↗

PubMed2003

Neural encoding in ventral striatum during olfactory discrimination learning.

A growing body of evidence implicates the ventral striatum in using information acquired through associative learning. The present study examined the activity of ventral striatal neurons in awake, behaving rats during go/no-go odor discrimination learning and reversal. Many neurons fired selectively to odor cues predictive of either appetitive (sucrose) or aversive (quinine) outcomes. Few neurons were selective when first exposed to the odors, but many acquired this differential activity as rats learned the significance of the cues. A substantial proportion of these neurons encoded the cues' learned motivational significance, and these neurons tended to reverse their firing selectivity after reversal of odor-outcome contingencies. Other neurons that became selectively activated during learning did not reverse, but instead appeared to encode specific combinations of cues and associated motor responses. The results support a role for ventral striatum in using the learned significance, both appetitive and aversive, of predictive cues to guide behavior.

Action Potentials↗

PubMed2002

Amygdalo-hypothalamic circuit allows learned cues to override satiety and promote eating.

Organisms eat not only in a response to signals related to energy balance. Eating also occurs in response to "extrinsic," or environmental, signals, including learned cues. Such cues can modify feeding based on motivational value acquired through association with either rewarding or aversive events. We provide evidence that a specific brain system, involving connections between basolateral amygdala and the lateral hypothalamus, is crucial for allowing learned cues (signals that were paired with food delivery when the animal was hungry) to override satiety and promote eating in sated rats. In an assessment of second-order conditioning, we also found that disconnection of this circuitry had no effect on the ability of a conditioned cue to support new learning. Knowledge about neural systems through which food-associated cues specifically control feeding behavior provides a defined model for the study of learning that may be informative for understanding mechanisms that contribute to eating disorders and more moderate forms of overeating.

Acoustic Stimulation↗

PubMed2002

Disconnection of the basolateral amygdala complex and nucleus accumbens impairs appetitive pavlovian second-order conditioned responses.

There is considerable evidence that the basolateral complex of the amygdala (ABL) is involved in learning about the motivational value of otherwise neutral stimuli. The authors examined the role in this function of the ABL and one of its major efferent structures. the nucleus accumbens. Male Long-Evans rats received either sham, ipsilaterally, or contralaterally placed unilateral lesions of the ABL and accumbens and were trained in an appetitive Pavlovian second-order conditioning task. Sham-lesioned and ipsilaterally lesioned rats acquired the task normally, but contralaterally lesioned rats, in which the ABL and accumbens were functionally disconnected, failed to acquire second-order conditioned responses (although they did acquire second-order conditioned orienting responses). The results suggest that the ABL and accumbens are part of a system critical for processing information about learned motivational value.

Amygdala↗

PubMed2002

The basolateral complex of the amygdala is necessary for acquisition but not expression of CS motivational value in appetitive Pavlovian second-order conditioning.

The basolateral complex of the amygdala (ABL) is involved in processing information about stimulus motivational value. However, it is not clear whether the ABL is critical for acquisition, maintenance, or expression of this information. Our previous work has shown that ABL lesions made prior to training, block acquisition of an appetitive Pavlovian second-order conditioning task, in which performance is thought to depend on the acquisition of motivational (conditioned reinforcement) value by the first-order conditioned stimulus (CS). The present experiments examined the effects of ABL lesions made after first-order conditioning, when the CS acquires motivational value, but before second-order conditioning, the test for acquired value of that CS. Rats received pairings of a visual CS with a food reinforcer. They then received bilateral sham or excitotoxic lesions of the ABL. After recovery, they received pairings of a second-order auditory CS with the previously conditioned visual CS. In two experiments, both sham and lesioned rats acquired normal second-order conditioned behaviours. Some of the same rats were then given another round of second-order conditioning with novel CSs. In this case, when first-order training occurred after surgery, some second-order conditioned behaviours were impaired in lesioned rats. Tests of the associative underpinnings of second-order conditioned behaviours showed that those behaviours impaired by ABL lesions were based on stimulus-response associations. The results show that although the ABL is critical for second-order conditioning, this role is limited to acquisition of information about the motivational value of the first-order CS, and it is not critical for maintenance of this information or for its use in forming second-order associations.

Acoustic Stimulation↗

PubMedDate not supplied

Lesions of orbitofrontal cortex and basolateral amygdala complex disrupt acquisition of odor-guided discriminations and reversals.

Recent work indicates that both orbitofrontal cortex (OFC) and the basolateral complex of the amygdala (ABL) are involved in processes by which cues are associated with predicted outcomes. To examine the respective roles of these structures in discrimination learning, rats with bilateral sham or neurotoxic lesions of either OFC or ABL were trained on a series of four 2-odor discrimination problems in a thirst-motivated go, no-go task. After acquisition of the series of odor problems, the rats were trained on serial reversals of the final odor problem. Performance on each problem was assessed by monitoring accuracy of choice behavior, and also by measuring latency to respond for fluid outcomes after odor sampling. During discrimination learning, rats in both lesioned groups had similar deficits, failing to show normal changes in response latency during learning, while at the same time exhibiting normal choice behavior relative to controls. Choice behavior was affected only during the reversal phase of training, in which OFC and ABL lesions produced distinctive deficits. Rats with ABL lesions were impaired on the first reversal (S1-/S2+), but were unimpaired at acquiring a reversal back to the original odor-outcome contigencies (S1+/S2-), whereas rats with OFC lesions were impaired on both types of reversals. These findings suggest that OFC and ABL serve partially overlapping roles in the use of incentive information that supports normal discrimination performance.

Amygdala↗