Biomedical subjects

Michela Gallagher

Publications and source records attributed to Michela Gallagher.

At least 19 recordsLinked to original sources

PubMed2006

Aging causes partial loss of basal forebrain but no loss of pontine reticular cholinergic neurons.

Cholinergic degeneration occurs in several neurodegenerative diseases. To investigate whether normal aging causes selective neurodegeneration, we compared counts of cholinergic neurons in the medial septum/vertical limb of the diagonal band and pedunculopontine and laterodorsal tegmental nuclei of the brainstem in young and aged Long-Evans rats characterized for their spatial learning ability in the Morris water maze. A subset of aged rats (aged-unimpaired) learned the spatial learning task as young rats, whereas another group (age-impaired) showed poorer learning than young animals. In the medial septum/diagonal band, there was a significant loss (-23%, P < 0.02) of cholinergic neurons in aged-impaired animals compared with young subjects. In the brainstem, there were no significant differences in cholinergic cell number in any group. This selective loss of cholinergic neurons may, in part, account for the cognitive deficits observed in aging and, considering previous findings in this model, may be related to oxidative stress.

Acetylcholine↗

PubMed2006

Learned contextual cue potentiates eating in rats.

Explicit cues associated with food consumption when hunger prevails will enhance eating when they are subsequently presented under conditions of satiety. Here we examined whether contextual conditioned stimuli (CSs) paired with consumption of food pellets while rats were food-deprived would enhance consumption of this food in rats that were not food-deprived. The conditioning context enhanced rats' consumption of the training food, but it did not change their consumption of the familiar, lab chow. These results show that the contextual CSs, like discrete cues, could modulate food consumption in a CS-potentiated eating paradigm. Furthermore, the data suggest that CS-potentiation of eating does not induce a general motivation to eat, akin to hunger, but instead more likely produces a more specific motivational state, akin to craving.

Animals↗

PubMed2006

Neurocognitive aging: prior memories hinder new hippocampal encoding.

Normal aging is often accompanied by impairments in forming new memories, and studies of aging rodents have revealed structural and functional changes to the hippocampus that might point to the mechanisms behind such memory loss. In this article, we synthesize recent neurobiological and neurophysiological findings into a model of the information-processing circuit of the aging hippocampus. The key point of the model is that small concurrent changes during aging strengthen the auto-associative network of the CA3 subregion at the cost of processing new information coming in from the entorhinal cortex. As a result of such reorganization in aged memory-impaired individuals, information that is already stored would become the dominant pattern of the hippocampus to the detriment of the ability to encode new information.

Aging↗

PubMed2006

Role of substantia nigra-amygdala connections in surprise-induced enhancement of attention.

Coding of prediction error by midbrain dopamine neurons has been examined extensively in the framework of associative learning theory. Most of this research has focused on the role of prediction error in determining the reinforcement value of unconditioned stimuli: poorly predicted ("surprising") outcomes are more effective reinforcers and produce a greater dopamine response than well predicted outcomes. However, surprise also enhances attention to cues that signal poorly predicted outcomes. Previous reports from our laboratories demonstrated that circuitry, including the amygdala central nucleus (CeA), the cholinergic neurons of the substantia innominata/nucleus basalis region, and their innervation of the posterior parietal cortex, is critical to these surprise-induced enhancements of attention in associative learning. The present study considered the origin of prediction error information important for the operation of this system by examining the effects of disrupting communication between the midbrain substantia nigra pars compacta (SNc) and the CeA. Rats received unilateral lesions of the SNc and lesions of the CeA in either the contralateral or ipsilateral hemisphere. Contralateral lesions eliminated the surprise-induced enhancement of attention and learning that was displayed by rats with ipsilateral control lesions. These results show that SNc-CeA communication is critical to mechanisms by which the coding of prediction error by midbrain dopamine neurons is translated into enhancement of attention and learning modulated by the cholinergic system.

Amygdala↗

PubMed2006

Muscarinic receptor-mediated GTP-Eu binding in the hippocampus and prefrontal cortex is correlated with spatial memory impairment in aged rats.

The present study examined muscarinic receptor/G-protein coupling in the hippocampus and the prefrontal cortex of young and aged Long-Evans rats characterized for spatial learning ability in the Morris water maze. In a highly sensitive time-resolved fluorometry GTP-Eu binding assay, muscarinic-mediated GTP-Eu binding was severely blunted in hippocampus (-32%) and prefrontal cortex (-34%) as a consequence of aging. Furthermore, the magnitude of decreased muscarinic-mediated GTP-Eu binding was significantly correlated with the severity of spatial learning impairment in hippocampus and prefrontal cortex of aged rats and was specifically decreased in the subset of aged rats that were spatial learning impaired when compared to the aged unimpaired and the young rats. Western blot data indicated a preservation of the membrane-bound M1 receptor and the Galphaq/11 protein in both brain regions. These data demonstrate that muscarinic signaling is severely impaired as a consequence of normal aging in a manner that is closely associated with age-related cognitive decline.

Age Factors↗

PubMed2006

Different roles for amygdala central nucleus and substantia innominata in the surprise-induced enhancement of learning.

Within most modern learning theories, the discrepancy between expected and obtained outcomes ("prediction error" or "surprise") is a critical determinant of the acquisition of learned associations. The results of studies from many laboratories show that the surprising omission of an expected event may enhance attention to stimuli that remain present, such that subsequent learning about those stimuli is enhanced. A series of reports from our laboratories demonstrated that these surprise-induced enhancements of stimulus associability depend on circuitry that includes the amygdala central nucleus (CeA), the cholinergic neurons in the sublenticular substantia innominata/nucleus basalis magnocellularis (SI/nBM), as well as certain cortical projections of these latter neurons. In this study, we found very different roles for CeA and SI/nBM in surprise-induced enhancements of stimulus associability. In four experiments that used transient inactivation techniques, we found that surprise-induced enhancement of subsequent learning about a stimulus depended on intact CeA function at the time of surprise but not when more rapid learning was subsequently expressed. In contrast, normal SI/nBM function was critical to the expression of enhanced learning but was not necessary when surprise was induced. These data suggest that these two components of the so-called "extended amygdala" serve distinct roles in the encoding and retrieval of information used in modulating attention to stimuli in associative learning. Additional circuitry linking these brain regions may also be important in the maintenance of that information.

Amygdala↗

PubMed2006

A specific amyloid-beta protein assembly in the brain impairs memory.

Memory function often declines with age, and is believed to deteriorate initially because of changes in synaptic function rather than loss of neurons. Some individuals then go on to develop Alzheimer's disease with neurodegeneration. Here we use Tg2576 mice, which express a human amyloid-beta precursor protein (APP) variant linked to Alzheimer's disease, to investigate the cause of memory decline in the absence of neurodegeneration or amyloid-beta protein amyloidosis. Young Tg2576 mice (< 6 months old) have normal memory and lack neuropathology, middle-aged mice (6-14 months old) develop memory deficits without neuronal loss, and old mice (> 14 months old) form abundant neuritic plaques containing amyloid-beta (refs 3-6). We found that memory deficits in middle-aged Tg2576 mice are caused by the extracellular accumulation of a 56-kDa soluble amyloid-beta assembly, which we term Abeta*56 (Abeta star 56). Abeta*56 purified from the brains of impaired Tg2576 mice disrupts memory when administered to young rats. We propose that Abeta*56 impairs memory independently of plaques or neuronal loss, and may contribute to cognitive deficits associated with Alzheimer's disease.

Alzheimer Disease↗

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

Multiple receptors coupled to phospholipase C gate long-term depression in visual cortex.

Long-term depression (LTD) in sensory cortices depends on the activation of NMDA receptors. Here, we report that in visual cortical slices, the induction of LTD (but not long-term potentiation) also requires the activation of receptors coupled to the phospholipase C (PLC) pathway. Using immunolesions in combination with agonists and antagonists, we selectively manipulated the activation of alpha1 adrenergic, M1 muscarinic, and mGluR5 glutamatergic receptors. Inactivation of these PLC-coupled receptors prevents the induction of LTD, but only when the three receptors were inactivated together. LTD is fully restored by activating any one of them or by supplying intracellular D-myo-inositol-1,4,5-triphosphate (IP3). LTD was also impaired by intracellular application of PLC or IP3 receptor blockers, and it was absent in mice lacking PLCbeta1, the predominant PLC isoform in the forebrain. We propose that visual cortical LTD requires a minimum of PLC activity that can be supplied independently by at least three neurotransmitter systems. This essential requirement places PLC-linked receptors in a unique position to control the induction of LTD and provides a mechanism for gating visual cortical plasticity via extra-retinal inputs in the intact organism.

Animals↗

PubMed2005

NMDA receptor-independent long-term depression correlates with successful aging in rats.

Some individuals maintain high cognitive functioning at older ages. Here we show that mechanisms for long-term depression differ in aged rodents that maintain cognitive performance compared to young adults. Our results imply that cognitive abilities may be sustained in aged individuals by a switch in synaptic plasticity mechanisms.

Adaptation, Physiological↗

PubMed2005

Amygdalar and prefrontal pathways to the lateral hypothalamus are activated by a learned cue that stimulates eating.

Experimental animals that are trained to associate a cue with food consumption when hunger prevails will subsequently consume a greater amount of food when that cue is presented under conditions of satiety. Previously, we showed that this phenomenon of conditioned potentiation of feeding is abolished by a neurotoxic lesion that encompasses the basolateral (BL), basomedial (BM), and lateral (LA) nuclei of the amygdala (AMY) and by disconnection of this region and lateral hypothalamus (LHA). Here, we combined immediate-early gene (IEG) and tract-tracing methods to map functional AMY-LHA circuitry that is engaged when potentiated feeding is produced by pavlovian conditioning. Sated rats were assessed for food consumption in the presence of a cue that was paired previously with food (CS+), or in the presence of another cue that was never paired with food (CS-), in two consecutive tests temporally arranged for activation of the effector IEGs Arc (activity-regulated cytoskeletal protein) and Homer 1a. We examined the selective induction of the IEGs by tests with CS+ or CS- presentations in AMY neurons that project to LHA, as identified with the retrograde tracer FluoroGold. Using the same labeling methods, we also examined neurons in several other forebrain regions, including the prefrontal cortex and nucleus accumbens, that receive strong inputs from BL/BM/LA nuclei and, in turn, innervate the LHA. Our results indicate that a cue that has acquired the ability to promote eating in sated rats (CS+) strongly activates a functional network formed by direct pathways from the BL/BM and orbitomedial prefrontal cortex to the LHA.

Amygdala↗

PubMed2005

Spatial memory in middle-aged female rats: assessment of estrogen replacement after ovariectomy.

Previous studies have shown that estrogen influences diverse aspects of neuronal function and morphology and modulates acquisition of various memory tasks in young adult female rodents. It is not clear whether estrogen is critical for optimal memory function in middle-aged female animals, i.e. when cyclicity gradually declines. We trained young adult (5 months) and older (10 months) female Long-Evans rats on a win-shift (delay) 12-arm radial maze (7 arms blocked pre-delay). Rats were preoperatively trained to criterion (< or =2 errors/trial for 3 days) with no delay then with a 60 s delay. All rats were ovariectomized when the age groups were 9 (Y) and 14 months (MA), respectively. Following recovery and retraining to criterion, each rat underwent consecutive treatment cycles with vehicle (Oil) or 17-beta-estradiol benzoate (E). Each 6-day acute treatment cycle, modeled after protocols previously shown to induce morphological and electrophysiological plasticity in the hippocampus at 24-48 h after estrogen injection, consisted of two consecutive daily injections of 10 microg E or Oil (0.1 ml subcutaneously) on Days 1-2 (Oil-Oil or E-E), testing on Days 3-4 at 60 s or 6 h delays, with Days 5-6 comprising of washout days. Each rat received a total of 4 treatment cycles, alternating between Oil and E cycles, in counterbalanced order. Estrogen treatment had no effect in either age group on pre-delay or post-delay errors at either 60 s or 6 h delays. The data indicate that the cyclic estrogen replacement regimen does not influence spatial memory function in young or middle-aged animals in the hippocampal-dependent appetitive radial maze task. Discussion of these unexpected results includes consideration of important experimental design factors that differ between our study and some previous reports, such as the extensive training and task experience our subject received prior to testing for estrogen effects.

Age Factors↗

PubMed2005

Age-associated alterations of hippocampal place cells are subregion specific.

Aging is associated with spatial memory impairments and with deficient encoding of information by the hippocampus. In young adult rats, recent studies on the firing properties of hippocampal neurons have emphasized the importance of the CA3 subregion in the rapid encoding of new spatial information. Here, we compared the spatial firing patterns of CA1 and CA3 neurons in aged memory-impaired rats with those of young rats as they explored familiar and novel environments. We found that CA1 place cells in aged and young rats had similar firing characteristics in the familiar and novel environments. In contrast, aged CA3 place cells had higher firing rates in general and failed to change their firing rates and place fields as much as CA3 cells of young rats when the rats were introduced to a novel environment. Thus, aged CA3 cells failed to rapidly encode new spatial information compared with young CA3 cells. These data suggest an important and selective contribution of CA3 dysfunction to age-related memory impairment.

Action Potentials↗

PubMed2005

Lesions of orbitofrontal cortex impair rats' differential outcome expectancy learning but not conditioned stimulus-potentiated feeding.

Patients with damage to the orbitofrontal cortex (OFC) display various impairments in cognitive and affective function, including a reduced ability to use information about the consequences of their actions to guide their behavior. In this study, rats with neurotoxic lesions of the OFC failed to use specific expectancies about outcomes to guide their learning of an instrumental discrimination task. In contrast, lesioned rats were unimpaired in a measure of learned motivational function, the potentiation of feeding under conditions of food satiation, by a conditioned stimulus that had been paired with food while the rats were food deprived. Notably, performance of both of these tasks has been shown to depend on the function of the basolateral amygdala (BLA), a region that is richly interconnected with the OFC. Thus, the present results are consistent with the view that the acquisition and use of specific outcome expectancies to guide behavior critically involve a neural system that includes the BLA and the OFC, but they indicate that certain motivational properties acquired by cues on the basis of appetitive learning involve BLA circuitry apart from the OFC.

Animals↗

PubMed2005

Rapid associative encoding in basolateral amygdala depends on connections with orbitofrontal cortex.

Certain goal-directed behaviors depend upon interactions between basolateral amygdala (ABL) and orbitofrontal cortex (OFC). Here we describe neurophysiological evidence of this cooperative function. We recorded from ABL in intact and OFC-lesioned rats during learning of odor discrimination problems and reversals. During learning, rats with ipsilateral OFC lesions exhibited a marked decline in the proportion of ABL neurons that fired differentially during cue sampling both before and after reversal and in the proportion of neurons that reversed odor preference when the odor-outcome associations were reversed. This decline appeared to reflect a loss of rapid flexibility in cue selectivity that characterized activity in intact rats. In addition, lesioned rats had fewer neurons that fired in anticipation of the predicted outcome during a delay period after responding but before outcome delivery. These findings support a role for OFC in facilitating the encoding of information about expected outcomes in ABL.

Amygdala↗

PubMed2005

Role of amygdalo-nigral circuitry in conditioning of a visual stimulus paired with food.

The amygdala central nucleus (CeA) plays an important part in associative learning. Although most research has focused on functions of its descending projections to brainstem areas involved in autonomic and somatomotor responses, the ascending projections of CeA also play critical roles in learning. For example, a CeA-nigrostriatal pathway is important for acquiring orienting responses (ORs) to conditioned stimuli (CSs) that signal food delivery. In this study, the function of this CeA-nigrostriatal pathway in appetitive conditioning of rats was considered in more detail. In experiment 1, we combined anatomical tracing and methods for detecting neuronal activation to examine whether CeA neurons that project to the substantia nigra pars compacta (SNc) are activated by a visual CS for food. After injection of the retrograde tracer Fluoro-Gold (FG) into SNc, the rats received pairings of a visual CS with food. After a test with the CS alone, the brains were prepared to assess FG labeling and CS-induced Fos expression in CeA with immunohistochemical procedures. Colocalization of Fos and FG in CeA neurons was visualized with confocal-fluorescence microscopy. The CS induced Fos expression in CeA, and a majority of these Fos-positive neurons were also FG positive, indicating activation of the CeA-SNc pathway by the CS. In experiment 2, lesions that disconnected CeA and SNc prevented the acquisition of conditioned ORs but did not affect the acquisition of conditioned food-related responses or the display of unconditioned ORs. These experiments demonstrate a role for amygdalo-nigral circuitry in learned modulation of attention to signals for biologically significant events.

Amygdala↗

PubMed2005

More is less: neurogenesis and age-related cognitive decline in Long-Evans rats.

A reduction in the ability to generate new neurons in the brain has been suggested to contribute to cognitive decline with advanced age. In an outbred model strain of Long-Evans rats, cognitive performance as a function of age is variable in assessments of hippocampal-dependent spatial memory. Recent research indicates that greater hippocampal neurogenesis accompanies diminished cognitive abilities in older Long-Evans rats. These findings imply that the role of neurogenesis might change between youth and old age, and that further work is needed to understand the potential benefits and liabilities that new neurons may afford an aging brain.

Age Factors↗

PubMed2005

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

In Pavlovian appetitive conditioning, rats often acquire 2 classes of conditioned responses: those whose form is determined by the reinforcer, and those whose form is determined by characteristics of the conditioned stimulus (CS). Consistent with the results of previous lesion studies, reversible inactivation of amygdala central nucleus function during pairings of an auditory CS with food prevented the acquisition of conditioned orienting responses specific to auditory CSs, whereas food-related conditioned behaviors were acquired normally. Neither inactivation nor posttraining neurotoxic lesions of the central nucleus affected the expression of previously acquired conditioned orienting. Thus, although the central nucleus is critical to the acquisition of information required for conditioned orienting to auditory cues, it is not needed for maintaining this information for later use.

Amygdala↗