Showing papers by "Michela Gallagher published in 1999"

Neural encoding in orbitofrontal cortex and basolateral amygdala during olfactory discrimination learning.

Abstract: Orbitofrontal cortex (OFC) is part of a network of structures involved in adaptive behavior and decision making. Interconnections between OFC and basolateral amygdala (ABL) may be critical for encoding the motivational significance of stimuli used to guide behavior. Indeed, much research indicates that neurons in OFC and ABL fire selectively to cues based on their associative significance. In the current study recordings were made in each region within a behavioral paradigm that allowed comparison of the development of associative encoding over the course of learning. In each recording session, rats were presented with novel odors that were informative about the outcome of making a response and had to learn to withhold a response after sampling an odor that signaled a negative outcome. In some cases, reversal training was performed in the same session as the initial learning. Ninety-six of the 328 neurons recorded in OFC and 60 of the 229 neurons recorded in ABL exhibited selective activity during evaluation of the odor cues after learning had occurred. A substantial proportion of those neurons in ABL developed selective activity very early in training, and many reversed selectivity rapidly after reversal. In contrast, those neurons in OFC rarely exhibited selective activity during odor evaluation before the rats reached the criterion for learning, and far fewer reversed selectivity after reversal. The findings support a model in which ABL encodes the motivational significance of cues and OFC uses this information in the selection and execution of an appropriate behavioral strategy.

Orbitofrontal Cortex and Representation of Incentive Value in Associative Learning

Abstract: Clinical evidence indicates that damage to ventromedial prefrontal cortex disrupts goal-directed actions that are guided by motivational and emotional factors. As a consequence, patients with such damage characteristically engage in maladaptive behaviors. Other research has shown that neurons in the corresponding orbital region of prefrontal cortex in laboratory animals encode information regarding the incentive properties of goals or expected events. The present study investigates the effect of neurotoxic orbitofrontal cortex (OFC) lesions in the rat on responses that are normally influenced by associations between a conditioned stimulus (CS) and the incentive value of reinforcement. Rats were first trained to associate a visual CS with delivery of food pellets to a food cup. As a consequence of learning, rats approached the food cup during the CS in anticipation of reinforcement. In a second training phase, injection of LiCl followed consumption of the food unconditioned stimulus (US) in the home cage, a procedure used to alter the incentive value of the US. Subsequently, rats were returned to the conditioning chamber, and their responding to the CS in the absence of the food US was tested. Lesions of OFC did not affect either the initial acquisition of a conditioned response to the light CS in the first training phase or taste aversion learning in the second training phase. In the test for devaluation, however, OFC rats exhibited no change in conditioned responding to the visual CS. This outcome contrasts with the behavior of control rats; after devaluation of the US a significant decrease occurred in approach to the food cup during presentation of the CS. The results reveal an inability of a cue to access representational information about the incentive value of associated reinforcement after OFC damage.

Heme oxygenase-2 is neuroprotective in cerebral ischemia

Abstract: Heme oxygenase (HO) is believed to be a potent antioxidant enzyme in the nervous system; it degrades heme from heme-containing proteins, giving rise to carbon monoxide, iron, and biliverdin, which is rapidly reduced to bilirubin. The first identified isoform of the enzyme, HO1, is an inducible heat-shock protein expressed in high levels in peripheral organs and barely detectable under normal conditions in the brain, whereas HO2 is constitutive and most highly concentrated in the brain. Interestingly, although HO2 is constitutively expressed, its activity can be modulated by phosphorylation. We demonstrated that bilirubin, formed from HO2, is neuroprotectant, as neurotoxicity is augmented in neuronal cultures from mice with targeted deletion of HO2 (HO2−/−) and reversed by low concentrations of bilirubin. We now show that neural damage following middle cerebral artery occlusion (MCAO) and reperfusion, a model of focal ischemia of vascular stroke, is substantially worsened in HO2−/− animals. By contrast, stroke damage is not significantly altered in HO1−/− mice, despite their greater debility. Neural damage following intracranial injections of N-methyl-d-aspartate (NMDA) is also accentuated in HO2−/− animals. These findings establish HO2 as an endogenous neuroprotective system in the brain whose pharmacologic manipulation may have therapeutic relevance.

Hippocampal lesions interfere with Pavlovian negative occasion setting

Abstract: Rats were trained with either a serial feature positive (L-->T1+ T-) or a serial feature negative (L-->T1-, T1+) discrimination, intermixed with training on another, nonconditional discrimination (T2+, N-), using a Pavlovian appetitive conditioning preparation with multiple response measures. Among rats trained with the serial feature positive discrimination, neurotoxic lesions of the hippocampus produced a transient impairment in the acquisition of that discrimination, but did not affect acquisition of the nonconditional discrimination. In contrast, among rats that received serial feature negative discrimination training, hippocampal lesions produced enduring deficits in the acquisition of both discriminations. The results of transfer tests indicated that both lesioned and control rats used a conditional learning strategy (occasion setting) to solve the feature positive and feature negative discriminations. Furthermore, lesioned rats, especially those that received training with the feature negative discrimination, displayed increasingly higher levels of general activity as training progressed. The results suggest that hippocampal lesions particularly interfere with inhibitory learning (negative occasion setting) about both explicit and contextual cues.

Metabotropic Glutamate Receptor-Mediated Hippocampal Phosphoinositide Turnover Is Blunted in Spatial Learning-Impaired Aged Rats

Abstract: Maximal phosphoinositide (PI) turnover was examined in the hippocampus of young and aged Long–Evans rats that were behaviorally characterized for spatial learning in the Morris water maze. The type 1 metabotropic glutamate receptor (mGluR) agonist 1S,3R ACPD was used to stimulate PI turnover and to determine the E MAX for each rat. Protein levels in hippocampus for type 1 mGluRs, Gαq11, and phospholipase Cβ-1 (PLCβ-1) were also measured by quantitative Western blotting. The results show that PI turnover mediated by the mGluRs was blunted in the aged rats. The magnitude of the decrement in PI turnover was also significantly correlated with age-related spatial memory decline. The decrease in mGluR-mediated PI turnover occurred without changes in the protein level of either the mGluRs or the G-protein coupled to those receptors, Gαq11. A significant decrease in the immunoreactivity of PLCβ-1, however, was observed in the hippocampus of aged rats; PLCβ-1 immunoreactivity was significantly correlated with spatial learning only when the young and aged rats were considered together. The decrement in mGluR-mediated signal transduction in the hippocampus that is related to cognitive impairment in aging may be attributable, at least in part, to a deficiency in the enzyme PLCβ-1. That deficiency may also contribute to a blunted response in muscarinic stimulation of hippocampal PI turnover that we previously found in this same study population. An age-related alteration in this signal transduction system may provide a functional basis for cognitive decline independent of any loss of neurons in the hippocampus.

Selective removal of cholinergic neurons in the basal forebrain alters cued target detection.

Abstract: A spatial orienting task was used to assess attention in rats with selective cholinergic lesions of the basal forebrain. The task required each rat to press a lever in response to a visual target that could occur in one of two locations. A target could be preceded by a cue that either accurately predicted the location of the target (valid) or appeared in the location opposite the target (invalid). Target detection was facilitated by valid cues and degraded by invalid cues in control rats. Performance of rats with lesions was equivalent to that of control rats for valid cues, but reflected an increased cost of invalid cueing. These data support a modulatory role for the basal forebrain cholinergic system in visuospatial attention.

Morphometric studies of the aged hippocampus: I. Volumetric analysis in behaviorally characterized rats

Abstract: The present investigation examined the structural integrity of the aged hippocampus by using computer-aided morphometry to quantify the volume of principal hippocampal circuits in young, mature adult, and aged Long-Evans rats. A key feature of the experimental design was that the status of hippocampal-dependent learning and memory was documented prior to histologic evaluation. The following regions, which were visualized by using Timm staining, were included in the analysis: 1) outer portions of the dentate gyrus molecular layer (OML) innervated by the lateral entorhinal cortex, 2) middle portions of the molecular layer (MML) that receive input from the medial entorhinal cortex, 3) the commissural/associational zone (IML) immediately adjacent to the granule cell layer, and 4) the hilus and mossy fiber projection to the CA3 pyramidal cell field (MF). To identify morphometric changes that emerge during the same segment of the life span as age-related learning impairment, analysis of the volumetric results focused on comparisons between the mature adult group and the aged group. Among the individual regions that were analyzed, age-related decreases in total volume were restricted to the MML. This effect, however, occurred against a background of other, subtle changes that, together, reflected substantial reorganization in the normal balance of hippocampal circuitry. Age-related decreases in the proportion of the molecular layer (ML) that comprises the MML were accompanied by a corresponding increase in relative IML volume. The ratio between the volumes of the MML and the MF also displayed significant age-related decline. Overall, aging affected septal levels of the hippocampus disproportionately, and, with the exception of MML/MF volume ratio, the temporal hippocampus was spared. Finally, the status of spatial learning among the aged animals correlated selectively with decreases in the MML/ML and MML/MF ratios. These results demonstrate that the effects of aging are regionally selective and circuit specific, and they suggest that connectional reorganization may contribute to age-related decline in the computational functions of the hippocampus. J. Comp. Neurol. 403:459‐470, 1999. r 1999 Wiley-Liss, Inc. Indexing terms: entorhinal cortex; histological techniques; maze learning; stereology

Open peer commentary No loss of synaptic proteins in the hippocampus of aged, behaviorally impaired rats<

Abstract: The levels of three different synaptic proteins in the hippocampus of young (6 months of age) and aged (26 ‐27 months of age) Long Evans rats were examined using quantitative Western blotting. An important feature to this study is that prior to the neurobiological analysis, hippocampal function was determined by assessing spatial learning ability in the Morris water maze. A subset of the aged rats was impaired on the learning task while the remaining aged cohort performed within the range of young rats. The amount of immunoreactivity for synaptophysin, synaptotagmin, and synaptosomal associated protein-25 did not differ between the young and aged rats. In addition, the aged rats with severe cognitive impairment had levels of these synaptic proteins that were similar to those of the aged rats with preserved cognitive function. This finding of no change in the levels of synaptic proteins suggests that substantial synapse loss in the hippocampal formation does not underlie cognitive decline in normal aging. © 1999 Elsevier Science Inc. All rights reserved.

Disconnection of the amygdala central nucleus and substantia innominata/nucleus basalis disrupts increments in conditioned stimulus processing in rats.

Abstract: Rats with a neurotoxic lesion of the amygdala central nucleus (CN) in one hemisphere and a 192 immunoglobulin G (192IgG)-saporin lesion of cholinergic neurons in the contralateral substantia innominata/nucleus basalis (SI/nBM) failed to show the enhanced attentional processing of a conditioned stimulus (CS) observed in sham-operated rats when that CS's predictive value was altered. Performance of these asymmetrically lesioned rats was poorer than that of rats with a unilateral lesion of either structure or with a symmetrical lesion of both structures in the same hemisphere. These results implicate connections between the CN and SI/nBM in the incremental attentional processing of CSs, extending previous research that has shown similar effects of bilateral lesions of either the CN or the SI/nBM.

Functions of the amygdala and related forebrain areas in attention and cognition.

Abstract: This paper will concentrate on two features of the systems described by Alheid and Heimer 1 that have influenced research in our laboratory in recent years. In the first part, we describe our findings on a representational function of the amygdaloid basolateral complex that appears to depend on its interconnections with the prefrontal cortex. In the second part, we describe progress assessing the function of magnocellular corticopetal neurons within the basal forebrain and the strong input to this system from the central amygdaloid group. These lines of behavioral research have revealed that subsystems in the basal forebrain and amygdala serve adaptive functions beyond the domains of motivation and emotion to include attention and cognition.

Impairments in conditioned stimulus processing and conditioned responding after combined selective removal of hippocampal and neocortical cholinergic input.

Abstract: Previous studies indicated that changes in attentional processing of conditioned stimuli (CSs) are regulated by the basal forebrain (BF) cholinergic system. In those studies, destruction of BF innervation of the neocortex interfered with enhancements in CS processing, and destruction of BF innervation of the hippocampus prevented reductions in CS processing. In the current experiments, the performance of rats with 192 IgG-saporin lesions of both hippocampal and neocortical cholinergic input was examined. These combined lesions disrupted both enhancements and reductions in CS processing. Lesioned rats also showed more general impairments in conditioned responding. These results indicate that, although the neural systems for increasing and decreasing attentional processing may be largely independent, combined loss of hippocampal and neocortical cholinergic input may produce behavioral impairments that are not apparent after either lesion alone.

Thalamic and basal forebrain cholinergic connections of the rat posterior parietal cortex

Abstract: THE thalamic connectivity and basal forebrain cholinergic input to the posterior parietal cortex (PPC) of Long-Evans rats was examined using combined retrograde tracing and immunocytochemical methods. As in previous studies, the PPC could be distinguished by its input from the lateral posterior, lateral dorsal, and posterior nuclei of the thalamus, but not the lateral geniculate nucleus or ventrobasal complex. These nuclei were also observed to receive reciprocal projections from the ipsilateral PPC. Cholinergic neurons innervating the PPC were primarily localized to the substantia innominata/nucleus basalis region. The implications of these data for possible functions of the cholinergic input to PPC are discussed.

Blocking can occur without losses in attention in rats with selective removal of hippocampal cholinergic input.

Abstract: Prior studies showed that 192 IgG-saporin lesions of cholinergic input to the hippocampus disrupted reductions in processing of uninformative stimuli. In 2 experiments in this study, the performance of rats with these lesions was examined in blocking procedures. In both lesioned and normal rats, previous pairing of one conditioned stimulus (CS) with food blocked conditioning of a 2nd CS when a compound of both CSs was paired with food. However, in subsequent savings tests, lesioned rats showed faster learning than did normal rats when the blocked CS was established as a signal for either reinforcement or nonreinforcement. Thus, the reduced attention to the blocked CS found in normal but not lesioned rats was not essential for the occurrence of blocking. Although rats with selective removal of hippocampal cholinergic input may be unable to reduce attention to redundant stimuli, other mechanisms of stimulus selection remain available to them.

Amygdala circuitry in attentional and representational

Abstract: The amygdala has long been implicated in the display of emotional behavior and emotional information processing, especially in the context of aversive events. In this review, we discuss recent evidence that links the amygdala to several aspects of foodmotivated associative learning, including functions often characterized as attention, reinforcement and representation. Each of these functions depends on the operation of separate amygdalar subsystems, through their connections with other brain systems. Notably, very different processing systems seem to be mediated by the central nucleus and basolateral amygdala, subregions of the amygdala that differ in their anatomy and in their connectivity. The basolateral amygdala is involved in the acquisition and representation of reinforcement value, apparently through its connections with ventral striatal dopamine systems and with the orbitofrontal cortex. The dentral nucleus, however, contributes heavily to attentional function in conditioning, by way of its influence on basal forebrain cholinergic systems and on the dorsolateral striatum.