Biomedical subjects

Michela Gallagher

Publications and source records attributed to Michela Gallagher.

At least 37 records · Page 2Linked to original sources

PubMed2005

Orbitofrontal lesions impair use of cue-outcome associations in a devaluation task.

The orbitofrontal cortex (OFC) has been implicated in the use of outcome expectancies to guide behavior. The present study used a devaluation task to examine this function. Rats first received light-food pairings followed by food-toxin pairings designed to devalue the food. After either excitotoxic or sham OFC lesions, responding to the light was reassessed. Sham-lesioned rats showed reduced responding to the light relative to behavioral controls, which had received food and toxin unpaired. In contrast, OFC-lesioned rats showed no such reductions. Combined with previous data (C. L. Pickens, M. P. Saddoris, B. Setlow, M. Gallagher, P. C. Holland, & G. Schoenbaum, 2003), these results indicate that the OFC is critical for the maintenance of information about the current incentive value of reinforcers or the use of that information to guide behavior.

Animal Feed↗

PubMed2004

Place cells of aged rats in two visually identical compartments.

Aged rats perform poorly on spatial learning tasks, a cognitive impairment which has been linked to the failure of hippocampal networks to fully encode changes in the external environment [Barnes CA, Suster MS, Shen J, McNaughton BL. Multistability of cognitive maps in the hippocampus of old rats. Nature 1997;388(6639):272-5; Wilson IA, Ikonen S, Gureviciene I, McMahan RW, Gallagher M, Eichenbaum H, et al. Cognitive aging and the hippocampus: how old rats represent new environments. J Neurosci 2004;24(15):3870-8]. To examine whether the impairment in hippocampal processing extends to conditions in which self-motion provides the cues for environmental change, we have analyzed spatial firing patterns of hippocampal pyramidal neurons in young and aged rats, as well as in young rats with selective cholinergic lesions, another model of cognitive aging. The rats walked between two visually identical environments, pitting self-motion cues that indicated environmental change against visual inputs that indicated no differences between environments. Our results indicated that place cells in both aged and cholinergic-lesioned rats were equally likely as those of young rats to create new spatial representations in the second compartment. These findings suggest that the hippocampal network of aged rats is able to process changes in internally generated cues without rigidity, but that incomplete processing of external landmark cues may lead to impaired spatial learning.

Action Potentials↗

PubMed2004

SGS742: the first GABA(B) receptor antagonist in clinical trials.

The GABA(B) receptor antagonist SGS742 (CGP36742) displays pronounced cognition enhancing effects in mice, young and old rats and in Rhesus monkeys in active and passive avoidance paradigms, in an eight-arm radial maze and a Morris water maze and in a social learning task. SGS742 blocks the late inhibitory postsynaptic potential and the paired-pulse inhibition of population spikes recorded from CA1 pyramidal neurons of the hippocampus of rats in vitro and in vivo. SGS742 significantly enhances the release of glutamate, aspartate, glycine and somatostatin in vivo. Chronic administration of SGS742 causes an up-regulation of GABA(B) receptors in the frontal cortex of rats. Single doses cause a significant enhancement of the mRNA and protein levels of NGF and BDNF in the cortex and hippocampus of rats. The observed antidepressant effects of SGS742 in rats may be explained by these findings. SGS742 was well tolerated in experimental animals as well as in young and elderly human volunteers with an absolute bioavailability in humans of 44%. In a Phase II double-blind, placebo-controlled study in 110 patients with mild cognitive impairment (MCI), oral administration of SGS742 at a dose of 600 mg t.i.d. for 8 weeks significantly improved attention, in particular choice reaction time and visual information processing as well as working memory measured as pattern recognition speed. A second Phase II clinical trial in 280 Alzheimer's disease patients is underway.

Adult↗

PubMed2004

Reduction in size of perforated postsynaptic densities in hippocampal axospinous synapses and age-related spatial learning impairments.

A central problem in the neurobiology of normal aging is why learning is preserved in some aged individuals yet impaired in others. To investigate this issue, we examined whether age-related deficits in spatial learning are associated with a reduction in postsynaptic density (PSD) area in hippocampal excitatory synapses (i.e., with a structural modification that is likely to have a deleterious effect on synaptic function). A hippocampus-dependent version of the Morris water maze task was used to separate Long-Evans male rats into young adult, aged learning-unimpaired, and equally aged learning-impaired groups. Axospinous synapses from the CA1 stratum radiatum were analyzed using systematic random sampling and serial section analyses. We report that aged learning-impaired rats exhibit a marked ( approximately 30%) and significant reduction in PSD area, whereas aged learning-unimpaired rats do not. The observed structural alteration involves a substantial proportion of perforated synapses but is not observed in nonperforated synapses. These findings support the notion that many hippocampal perforated synapses become less efficient in aged learning-impaired rats, which may contribute to cognitive decline during normal aging.

Aging↗

PubMed2004

Cognitive aging and the hippocampus: how old rats represent new environments.

Spatial learning impairment in aged rats is associated with changes in hippocampal connectivity and plasticity. Several studies have explored the age-related deficit in spatial information processing by recording the location-specific activity of hippocampal neurons (place cells). However, these studies have generated disparate characterizations of place cells in aged rats as unstable (Barnes et al., 1997), resistant to change (Tanila et al., 1997b; Oler and Markus, 2000; Wilson et al., 2003), or delayed in using external cues (Rosenzweig et al., 2003). To reconcile these findings, we recorded place cells from aged and young rats as they repeatedly explored both a highly familiar environment and an initially novel environment, and we repeatedly tested whether the place fields formed in the novel environment were anchored by external cues. Initially, spatial representations in aged rats were abnormally maintained between the familiar and novel environments. Then, new representations were formed but were also delayed in becoming anchored to the external landmarks. Finally, even when the new spatial representations became bound to the landmarks, they were multi-stable across repetitive exposures to the formerly novel environment. These observations help to reconcile previously divergent characterizations of spatial representation in aged rats and suggest a model of cognitive aging and hippocampal function.

Aging↗

PubMed2004

Amygdala-frontal interactions and reward expectancy.

Recent evidence indicates that networks including the amygdala and prefrontal cortex provide a key interface between affect and cognition. Converging evidence from rodents, humans, and non-human primates indicates that interconnections between the basolateral complex of the amygdala and the orbitofrontal cortex are crucial to the formation and use of expectancies of reinforcers in the guidance of goal-directed behavior.

Amygdala↗

PubMed2004

Amygdala central nucleus function is necessary for learning but not expression of conditioned visual orienting.

When exposed to pairings of a visual stimulus with food delivery, rats normally acquire both conditioned orienting responses directed toward the visual stimulus and conditioned food-related responses. Consistent with the results of previous lesion studies, reversible inactivation of amygdala central nucleus function before each conditioning session prevented the acquisition of conditioned orienting responses, whereas food-related behaviors were acquired normally. By contrast, neither inactivation nor neurotoxic lesions of central nucleus affected the expression of previously acquired conditioned orienting responses. Thus, the central nucleus is apparently not critical to the maintenance of information required for conditioned orienting, but instead is necessary for memory storage elsewhere. Specialized roles for components of a circuit for conditioned orienting, which includes the central nucleus, the substantia nigra, and dorsolateral striatum, are discussed.

Amygdala↗

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

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↗

PubMed2003

Phosphorylation of the AMPA receptor GluR1 subunit is required for synaptic plasticity and retention of spatial memory.

Plasticity of the nervous system is dependent on mechanisms that regulate the strength of synaptic transmission. Excitatory synapses in the brain undergo long-term potentiation (LTP) and long-term depression (LTD), cellular models of learning and memory. Protein phosphorylation is required for the induction of many forms of synaptic plasticity, including LTP and LTD. However, the critical kinase substrates that mediate plasticity have not been identified. We previously reported that phosphorylation of the GluR1 subunit of AMPA receptors, which mediate rapid excitatory transmission in the brain, is modulated during LTP and LTD. To test if GluR1 phosphorylation is necessary for plasticity and learning and memory, we generated mice with knockin mutations in the GluR1 phosphorylation sites. The phosphomutant mice show deficits in LTD and LTP and have memory defects in spatial learning tasks. These results demonstrate that phosphorylation of GluR1 is critical for LTD and LTP expression and the retention of memories.

Animals↗

PubMed2003

Lesions of basolateral amygdala impair extinction of CS motivational value, but not of explicit conditioned responses, in Pavlovian appetitive second-order conditioning.

The basolateral amygdala (BLA) is important for the modification of the motivational significance of events through associative learning. In previous work, we found that BLA was critical for the acquisition of conditioned reinforcement value to a visual conditioned stimulus (CS) paired with food. Unlike normal rats, rats with neurotoxic lesions of the BLA failed to acquire Pavlovian second-order conditioning to an auditory stimulus paired with the first-order visual CS in the absence of food. In this experiment, we examined the role of BLA in the extinction of the previously acquired conditioned reinforcement value of a Pavlovian CS. Rats received first-order visual CS-food pairings prior to either BLA- or sham-lesions. Subsequent CS-alone extinction training reduced the ability of the visual CS to reinforce second-order conditioning of an auditory stimulus in the sham-lesioned rats, but not in the BLA-lesioned rats. Despite this persistence of the conditioned reinforcement value of the visual first-order CS in the BLA-lesioned rats, no effects of the lesions were observed on extinction of the explicit behavioural conditioned responses elicited by that CS.

Amygdala↗

PubMed2003

Double dissociation of the effects of lesions of basolateral and central amygdala on conditioned stimulus-potentiated feeding and Pavlovian-instrumental transfer.

Pavlovian conditioned stimuli (CSs) for food can enhance both the performance of instrumental responses that earn food (Pavlovian-instrumental transfer; PIT) and the consumption of food itself (CS-potentiated feeding). After a single phase of Pavlovian training, each rat was tested in both PIT and potentiated feeding tasks. Rats with lesions of the central nucleus of the amygdala failed to exhibit PIT but showed normal CS-potentiated feeding. By contrast, rats with lesions of the basolateral amygdala showed normal PIT but failed to display CS-potentiated feeding. Performances in a variety of comparison conditions suggested that both lesion effects reflected impairment of acquired motivational functions, rather than with attentional processes or the display of specific learned responses. Implications of the double dissociation of these two aspects of Pavlovian conditioned incentive motivation for amygdala function in associative learning are considered.

Amygdala↗

PubMed2003

Amygdala subsystems and control of feeding behavior by learned cues.

A combination of behavioral studies and a neural systems analysis approach has proven fruitful in defining the role of the amygdala complex and associated circuits in fear conditioning. The evidence presented in this chapter suggests that this approach is also informative in the study of other adaptive functions that involve the amygdala. In this chapter we present a novel model to study learning in an appetitive context. Furthermore, we demonstrate that long-recognized connections between the amygdala and the hypothalamus play a crucial role in allowing learning to modulate feeding behavior. In the first part we describe a behavioral model for motivational learning. In this model a cue that acquires motivational properties through pairings with food delivery when an animal is hungry can override satiety and promote eating in sated rats. Next, we present evidence that a specific amygdala subsystem (basolateral area) is responsible for allowing such learned cues to control eating (override satiety and promote eating in sated rats). We also show that basolateral amygdala mediates these actions via connectivity with the lateral hypothalamus. Lastly, we present evidence that the amygdalohypothalamic system is specific for the control of eating by learned motivational cues, as it does not mediate another function that depends on intact basolateral amygdala, namely, the ability of a conditioned cue to support new learning based on its acquired value. Knowledge about neural systems through which food-associated cues specifically control feeding behavior provides a defined model for the study of learning. In addition, this model may be informative for understanding mechanisms of maladaptive aspects of learned control of eating that contribute to eating disorders and more moderate forms of overeating.

Amygdala↗

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

The effects of amygdala lesions on conditioned stimulus-potentiated eating in rats.

Both control rats and rats with neurotoxic lesions of the amygdala central nucleus ate more food during presentations of a conditioned stimulus (CS) previously paired with food than during an unpaired CS. This potentiation occurred regardless of whether the food was presented in its usual place or in a different location. By contrast, rats with neurotoxic lesions of basolateral amygdala showed no evidence for conditioned potentiation of eating. These results are considered in the context of anatomical projections from these amygdalar areas to other brain regions involved in feeding, and the role of amygdala subregions in the acquisition of motivational value in conditioning.

Amygdala↗

PubMed2002

Individual differences in spatial memory among aged rats are related to hippocampal PKCgamma immunoreactivity.

We reported previously that the extent of spatial memory impairment among aged rats was correlated positively with levels of protein kinase Cgamma in hippocampal homogenates measured by quantitative Western blotting (Colombo et al., 1997). In the current study, immunocytochemistry was used to test whether the relationship between elevated PKC-gamma and memory impairment among aged rats could be localized further within regions of the hippocampus. Six- and 24-month-old male Long-Evans rats were first trained in the water maze on a standard place-learning task and then trained 2 weeks later on a transfer task designed for rapid acquisition. In comparison with young rats, aged rats with impaired spatial memory had increased PKCgamma-immunoreactivity (PKCgamma-ir) in CA1 of the hippocampus, but not the dentate gyrus. In addition, PKCgamma-ir in CA1 was correlated positively with spatial memory impairment among aged rats on the standard place-learning and the transfer training tasks. The current results are consistent with our previous report of PKCgamma in hippocampal homogenates, and show further that the relationships between PKCgamma-ir and memory impairments among aged rats are most evident in area CA1. Thus age-related impairments of spatial memory, as well as deficits in the flexible use of previously acquired information, may result from dysregulation of PKCgamma.

Aging↗

PubMed2002

Cholinergic system regulation of spatial representation by the hippocampus.

The role of the basal forebrain cholinergic system in hippocampal spatial representation was explored by examining the effects of immunotoxic lesions of the septo-hippocampal cholinergic neurons on the firing patterns of hippocampal place cells as rats explored familiar and novel environments. In a highly familiar environment, the basic qualities and stability of place fields were unaffected by the lesion. When first exposed to a set of novel environmental cues without otherwise disorienting the animals, place cells in both normal and lesioned animals responded with similar alterations in their firing patterns. Upon subsequent repetitive exposures to the new environment, place cells of normal rats developed a spatial representation distinct from that of the familiar environment. By contrast, place cells of lesioned animals reconverged in the direction of the representation associated with the familiar environment. These results suggest that cholinergic input may determine whether new visual information or a stored representation of the current environment will be actively processed in the hippocampal network.

Animals↗