Neurotoxic Lesions Research Articles

Long‐term survival of olfactory sensory neurons after target depletion

Life-long addition and elimination of neurons within the adult olfactory epithelium and olfactory bulb allows for adaptive structural responses to sensory experience, learning, and recovery after injury. The interdependence of the two structures is highlighted by the shortened life span of sensory neurons deprived of bulb contact, and has prompted the hypothesis that trophic cues from the bulb contribute to their survival. The specific identity and source of these signals remain unknown. To investigate the potential role of target neurons in this support, we employed a neurotoxic lesion to selectively remove them while preserving the remaining nerve projection pathway, and examined the dynamics of sensory neuron proliferation and survival. Pulse-labeling of progenitors with bromodeoxyuridine showed that, as with surgical bulb removal, increased apoptosis in the epithelium triggered accelerated production of new neurons after chemical depletion of target cells. Rather than undergoing premature death, a large subpopulation of these neurons survived long term. The combination of increased proliferation and extended survival resulted in essentially normal numbers of new sensory neurons surviving for as long as 5 weeks, with an accompanying restoration of olfactory marker protein expression. Changes in neurotrophic factor expression levels as measured by quantitative polymerase chain reaction (Q-PCR), and in bulb cell populations, including the addition of new neurons generated in the subventricular zone, were observed in the injured bulb. These data indicate that olfactory sensory neurons can adapt to reductions in their normal target field by obtaining sufficient support from remaining or alternative cell sources to survive and maintain their projections.

The septo-hippocampal system, learning and recovery of function

We understand this review as an attempt to summarize recent advances in the understanding of cholinergic function in cognition. Such a role has been highlighted in the 1970s by the discovery that dementia patients have greatly reduced cholinergic activity in cortex and hippocampus. A brief anatomical description of the major cholinergic pathways focuses on the basal forebrain and its projections to cortex and hippocampus. From this distinction, compelling evidence suggests that the basal forebrain → cortex projection regulates the excitability of principal cortical neurons and is thereby critically involved in attention, stimulus detection and memory function, although the biological conditions for these functions are still debated. Similar uncertainties remain for the septo-hippocampal cholinergic system. Although initial lesions of the septum caused memory deficits reminiscent of hippocampal ablations, recent and more refined neurotoxic lesion studies which spared non-cholinergic cells of the basal forebrain failed to confirm these memory impairments in experimental animals despite a near total loss of cholinergic labeling. Yet, a decline in cholinergic markers in aging and dementia still stands as the most central piece of evidence for a link between the cholinergic system and cognition and appear to provide valuable targets for therapeutic approaches.

Post‐training excitotoxic lesions of the dorsal hippocampus attenuate generalization in auditory delay fear conditioning

An abundance of evidence indicates a role for the dorsal hippocampus (DH) in learning and memory. Pavlovian fear conditioning provides a useful model system in which to investigate DH function because conditioning to polymodal contextual cues, but generally not to discrete unimodal cues, depends upon the integrity of the DH. There is some suggestion that the hippocampus may be involved in generalization to discrete auditory stimuli following conditioning, but the available literature offers conflicting results regarding the nature of hippocampus involvement. The present experiments were designed to address a role for the DH in auditory generalization following delay fear conditioning. Rats were trained with two or 16 trials of delay fear conditioning and subsequently given a neurotoxic lesion of the DH or sham surgery. Upon recovery, they were tested for fear conditioned responding to the auditory stimulus they were trained with, as well as generalized responding to a novel auditory stimulus. Sham animals showed substantial generalization to the novel stimulus when trained with two or 16 trials. However, lesion animals showed much less generalization (better discriminative performance) to the novel stimulus following 16 conditioning trials while still showing substantial fear conditioned freezing to the trained stimulus. A second experiment showed that this effect was not the result of a non-associative response to the novel stimulus. We conclude that, with extended training, animals become capable of discriminating between trained and novel stimuli but another hippocampus-dependent process maintains generalized responding.

Patterns of retrograde amnesia for recent and remote incidental spatial learning in rats

A non-navigational test of incidental spatial learning was used to determine whether hippocampal damage causes temporally-graded retrograde amnesia (TGRA) for allocentric-spatial information. Rats were exposed to two identical objects in a circular open field for 7 min on seven consecutive days. In the 1-3 days after the last day of familiarization, rats received neurotoxic lesions of the hippocampal formation (HPC) or sham lesions. Another two groups received the same lesions 3 weeks after familiarization. The rats were then placed back in the open field with one object displaced, and the time spent in each of the quadrants as well as time spent exploring the objects was recorded. Rats that received HPC lesions 3 weeks but not 1-3 days after familiarization showed evidence of preserved remote spatial memory; however, their remote memory was expressed through different behavior than control rats. Rats with HPC lesions spent more time with the displaced object than with the object that remained in the same place, whereas control rats spent more time in the quadrant where the displaced object used to be. These results suggest that remote spatial memories may be preserved with a sufficiently long familiarization-to-surgery interval before HPC lesions, but that the nature of these memories may differ in quantity and/or quality from those of intact rats.

Selective Aspiration or Neurotoxic Lesions of Orbital Frontal Areas 11 and 13 Spared Monkeys' Performance on the Object Discrimination Reversal Task

Damage to the orbital frontal cortex (OFC) has long been associated with reversal learning deficits in several species. In monkeys, this impairment follows lesions that include several OFC subfields. However, the different connectional patterns of OFC subfields together with neuroimaging data in humans have suggested that specific OFC areas play distinctive roles in processing information necessary to guide behavior (Kringelbach and Rolls, 2004; Barbas, 2007; Price, 2007). More specifically, areas 11 and 13 contribute to a sensory network, whereas medial areas 10, 14, and 25 are heavily connected to a visceromotor network. To examine the contribution of areas 11 and 13 to reversal learning, we tested monkeys with selective damage to these two OFC areas on two versions of the ODR task using either one or five discrimination problems. We compared their performance with that of sham-operated controls and of animals with neurotoxic amygdala lesions, which served as operated controls. Neither damage to areas 11 and 13 nor damage to the amygdala affected performance on the ODR tasks. The results indicate that areas 11 and 13 do not critically contribute to reversal learning and that adjacent damage to OFC subfields (10, 12, 14, and 25) could account for the ODR deficits found in earlier lesion studies. This sparing of reversal learning will be discussed in relation to deficits found in the same animals on tasks that measure behavioral modulation when relative value of affective (positive and negative) stimuli was manipulated.

Transforming growth factor-alpha induces neurogenesis and behavioral improvement in a chronic stroke model

Transforming growth factor-alpha (TGFα) is a powerful endogenous mitogen and neurotrophic factor, which has previously been shown to induce a massive proliferative response in the brains of Parkinson's disease model rats injured by an acute neurotoxic lesion. We now show that TGFα can also produce a massive proliferative response in rat brains subjected to stroke caused by a middle cerebral artery occlusion (MCAO), even when the growth factor is administered as late as 4 weeks after injury. This combination of stimuli provokes DNA synthesis, shown by 5′-bromo-2-deoxyuridine incorporation, throughout the ependymal layer and subventricular zone (SVZ) of the forebrain during the 4 weeks of growth factor administration. The newly generated cells migrate preferentially along and ventral to the corpus callosum (CC) and external capsule to the site of the injury where many of them differentiate into several site-appropriate neuronal phenotypes in association with near complete (99%) behavioral recovery. We conclude that the injury response of endogenous neural stem cells as well as behavioral recovery can be significantly enhanced by application of TGFα, and that this approach represents a potential therapeutic strategy for chronic stroke and other neurological damage in human patients.

Head direction cell instability in the anterior dorsal thalamus after lesions of the interpeduncular nucleus.

Previous research has identified a population of cells throughout the limbic system that discharge as a function of the animal's head direction (HD). Altering normal motor cues can alter the HD cell responses and disrupt the updating of their preferred firing directions, thus suggesting that motor cues contribute to processing the HD signal. A pathway that conveys motor information may stem from the interpeduncular nucleus (IPN), a brain region that has reciprocal connections with HD cell circuitry. To test this hypothesis, we produced electrolytic or neurotoxic lesions of the IPN and recorded HD cells in the anterior dorsal thalamus (ADN) of rats. Direction-specific firing remained present in the ADN after lesions of the IPN, but measures of HD cell properties showed that cells had reduced peak firing rates, large directional firing ranges, and firing that predicted the animal's future heading more than in intact controls. Furthermore, preferred firing directions were moderately less influenced by rotation of a salient visual landmark. Finally, the preferred directions of cells in lesioned rats exhibited large shifts when the animals foraged for scattered food pellets in a darkened environment and when locomoting from a familiar environment to a novel one. We propose that the IPN contributes motor information about the animal's movements to the HD cell circuitry. Furthermore, these results suggest that the IPN plays a broad role in the discharge properties and stability of direction-specific activity in the HD cell circuit.

Alterations of Taste Reactivity after Neurotoxic Lesions in the Prefrontal Cortex

Alterations of Taste Reactivity after Neurotoxic Lesions in the Prefrontal Cortex

Does the amygdalo-nigro-striatal circuit underlie fear-evoked temporal distortion?

Event Abstract Back to Event Does the amygdalo-nigro-striatal circuit underlie fear-evoked temporal distortion? Mouna Es-seddiqi1*, B. L. Brown2, Nicole El-Massioui1 and Valerie Doyere1 1 CNRS UMR 8620, Laboratoire de Neurobiologie de l'Apprentissage, de la Memoire et de la Communication, France 2 Queens College, Department of Psychology, United States Time perception is known to be altered by emotion. However, neither the underlying mechanisms of this effect, nor the neural networks involved, are understood. Here, we ask whether the amygdalo-nigro-striatal circuit mediates the impact of emotion on temporal perception. Four groups of rats were prepared: the first group (Contra) with crossed lesions consisting of a neurotoxic lesion of the medial part of the central nucleus of the amygdala (CeA) in one hemisphere and a dopaminergic lesion of the nigrostriatal pathway in the contralateral hemisphere. The second group (Ipsi) was with CeA and nigrostriatal lesions in the same hemisphere; a group (Amy) with bilateral CeA lesions. The third group was sham-operated rats (Sham). Animals were trained on a temporal discrimination procedure in which one response ("short") was reinforced following a 2-sec tone signal and a different response ("long") was reinforced following an 8-sec tone signal. Temporal perception was then examined using bisection tests with added unreinforced signals of intermediate duration. The effect of a fear cue on temporal perception was tested by introducing a previously fear conditioned light prior to the tone signal on some trials. The data showed that the bisection function was shifted toward the right in the Contra and Ipsi rats, but not in CeA rats. The fear cue altered the temporal sensitivity in Sham, Ipsi and Contra groups, but not in CeA rats. These data support the interpretation that the dopaminergic nigrostriatal projection is crucial to duration discrimination in the seconds-to-minutes range. However, the impact of negative emotion on time perception is mediated via the central nucleus, but bypasses the nigrostriatal circuit. Funding: ANR-MEMOTIME, LIA-EmoTime Keywords: amygdalo-nigro-striatal circuit, emotion, Time Perception Conference: 3rd Mediterranean Conference of Neuroscience , Alexandria, Egypt, 13 Dec - 16 Dec, 2009. Presentation Type: Poster Presentation Topic: Stress Citation: Es-seddiqi M, Brown BL, El-Massioui N and Doyere V (2009). Does the amygdalo-nigro-striatal circuit underlie fear-evoked temporal distortion?. Front. Neurosci. Conference Abstract: 3rd Mediterranean Conference of Neuroscience . doi: 10.3389/conf.neuro.01.2009.16.148 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 25 Nov 2009; Published Online: 25 Nov 2009. * Correspondence: Mouna Es-seddiqi, CNRS UMR 8620, Laboratoire de Neurobiologie de l'Apprentissage, de la Memoire et de la Communication, Orsay, France, esseddiqimouna@yahoo.fr Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Mouna Es-seddiqi B. L Brown Nicole El-Massioui Valerie Doyere Google Mouna Es-seddiqi B. L Brown Nicole El-Massioui Valerie Doyere Google Scholar Mouna Es-seddiqi B. L Brown Nicole El-Massioui Valerie Doyere PubMed Mouna Es-seddiqi B. L Brown Nicole El-Massioui Valerie Doyere Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

Does fear disrupt temporal perception via the amygdalo-nigro-striatal circuit?

Event Abstract Back to Event Does fear disrupt temporal perception via the amygdalo-nigro-striatal circuit? M. Es-seddiqi1*, B. L. Brown2, Nicole El-Massioui1 and Valerie Doyere1 1 Universite Paris Sud, Laboratoire de Neurobiologie de l’Apprentissage, France 2 Queens College, Department of Psychology, United States Time perception is known to be altered by emotion. However, neither the underlying mechanisms of this effect, nor the neural networks involved, are understood. Here, we ask whether the amygdalo-nigro-striatal circuit mediates the impact of emotion on temporal perception. Four groups of rats were prepared: a group (Contra) with crossed lesions consisting of a neurotoxic lesion of the medial part of the central nucleus of the amygdala (CeA) in one hemisphere and a dopaminergic lesion of the nigrostriatal pathway in the contralateral hemisphere; a group (Ipsi) with CeA and nigrostriatal lesions in the same hemisphere; a group (Amy) with bilateral CeA lesions; a group of sham-operated rats (Sham). Animals were trained on a temporal discrimination procedure in which one response ("short") was reinforced following a 2-sec tone signal and a different response ("long") was reinforced following an 8-sec tone signal. Temporal perception was then examined using bisection tests with added unreinforced signals of intermediate duration. The effect of a fear cue on temporal perception was tested by introducing a previously fear conditioned light prior to the tone signal on some trials. The data showed that the bisection function was shifted toward the rightwith no change in sensitivity to time in the Contra and Ipsi rats, but not in CeA rats, suggesting an underestimation of time in dopaminergic lesioned animals. The fear cue altered the temporal sensitivity in Sham, Ipsi and Contra groups, but not in CeA rats, suggesting that only the bilateral lesion of the central amydala suppressed the effect of emotion on time perception. These data support the interpretation that the dopaminergic nigrostriatal projection, but not the central nucleus of amygdala, is crucial to duration discrimination in the seconds-to-minutes range. Our results also suggest that the impact of negative emotion on time perception is mediated via the central nucleus, but bypasses the nigrostriatal circuit.Funding: ANR-MEMOTIME; LIA-EmoTime Conference: 41st European Brain and Behaviour Society Meeting, Rhodes Island, Greece, 13 Sep - 18 Sep, 2009. Presentation Type: Poster Presentation Topic: Poster presentations Citation: Es-seddiqi M, Brown BL, El-Massioui N and Doyere V (2009). Does fear disrupt temporal perception via the amygdalo-nigro-striatal circuit?. Conference Abstract: 41st European Brain and Behaviour Society Meeting. doi: 10.3389/conf.neuro.09.2009.12.023 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 24 Sep 2009; Published Online: 24 Sep 2009. * Correspondence: M. Es-seddiqi, Universite Paris Sud, Laboratoire de Neurobiologie de l’Apprentissage, Orsay, France, mouna.es-seddiqi@u-psud.fr Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers M. Es-seddiqi B. L Brown Nicole El-Massioui Valerie Doyere Google M. Es-seddiqi B. L Brown Nicole El-Massioui Valerie Doyere Google Scholar M. Es-seddiqi B. L Brown Nicole El-Massioui Valerie Doyere PubMed M. Es-seddiqi B. L Brown Nicole El-Massioui Valerie Doyere Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

Neurotoxic lesion of the rostral perirhinal cortex blocks stress-induced exploratory behavioral changes in male rats

Exposure to stress leads to adaptive responses including both behavioral and physiological changes. This process is induced by the activation of multiple brain regions. The present study examined the role of the rostral perirhinal cortex (rPRh) in behavioral changes following electrical foot shock-induced stress. The rPRh of rats was lesioned bilaterally by local microinjections of 10 μg N-methyl-d-aspartic acid (NMDA) before foot shocks (0.7 mA, 1 s). The effects of these lesions on foot shock-induced changes in exploratory behaviors were tested in the open field (4 h, 48 h, 72 h, and 14 days after foot shocks) and the light–dark box (7 days after foot shocks). Foot-shocked and sham-lesioned rats showed several well known behavioral changes in the open field (e.g., immobility, reduction of exploratory activity) most marked at 48 h after foot shocks, and the light–dark box (e.g., reduction of time spent and activity in the lit compartment). All these stress-induced behavioral changes were blocked by neurotoxic lesions of the rPRh. Furthermore, rPRh lesions did not affect behavior in the open field and the light–dark box in unstressed rats. Taken together, these data indicate that the rPRh is involved in neurophysiological mechanisms that mediate changes induced by foot-shock stress in exploratory behaviors which indicate unconditioned fear or anxiety.

Associative structure of fear memory after basolateral amygdala lesions in rats.

The authors have recently demonstrated that rats with basolateral amygdala (BLA) lesions acquire Pavlovian fear conditioning after overtraining. However, it is not known whether the associative basis of Pavlovian fear memory acquired by rats with BLA lesions is similar to that of intact rats. Associations are typically formed between the conditional (CS) and unconditional (US) stimuli (stimulus-stimulus; S-S), although it is possible for stimuli to enter into association with the responses they produce (stimulus-response; S-R). Indeed, the central nucleus of the amygdala, which is essential for fear conditioning in rats with BLA lesions, may mediate S-R associations in some Pavlovian tasks. The authors therefore used a postconditioning US inflation procedure (i.e., exposure to intense footshock USs) to assess the contribution of S-S associations to fear conditioning after overtraining in rats with BLA lesions. In Experiment 1, intact rats that were overtrained and later inflated displayed elevated freezing levels when tested, indicating that S-S associations contribute to overtrained fear memories. Interestingly, neither neurotoxic BLA lesions nor temporary inactivation of the BLA during overtraining prevented the inflation effect (Experiment 2 and 3, respectively). These results reveal that S-S associations support Pavlovian fear memories after overtraining in both intact rats and rats with BLA lesions, and imply that the central nucleus of the amygdala encodes CS-US associations during fear conditioning.

Transient and selective overexpression of D 2 receptors in the striatum causes persistent deficits in conditional associative learning

Cognitive deficits in schizophrenia are thought to derive from a hypofunction of the prefrontal cortex (PFC), but the origin of the hypofunction is unclear. To explore the nature of this deficit, we genetically modified mice to model the increase in striatal dopamine D(2) receptors (D(2)Rs) observed in patients with schizophrenia. Previously, we reported deficits in spatial working memory tasks in these mice, congruent with the working memory deficits observed in schizophrenia. However, patients with schizophrenia suffer from deficits in many executive functions, including associative learning, planning, problem solving, and nonspatial working memory. We therefore developed operant tasks to assay two executive functions, conditional associative learning (CAL) and nonspatial working memory. Striatal D(2)R-overexpressing mice show a deficit in CAL because of perseverative behavior, caused by interference from the previous trial. D(2)R up-regulation during development was sufficient to cause this deficit, because switching off the transgene in adulthood did not rescue the phenotype. We validated prefrontal dependency of CAL by using neurotoxic lesions. Lesions of the medial PFC including the anterior cingulate, infralimbic, and prelimbic cortices impair CAL because of increased interference from previously rewarded trials, exactly as observed in D(2)R transgenic mice. In contrast, lesions restricted to the infralimbic and prelimbic cortices have no effect on CAL but impair performance in the nonspatial working memory task. These assays not only give us insight into how excess striatal D(2)Rs affect cognition but also provide tools for studying cognitive endophenotypes in mice.

Auditory trace fear conditioning requires perirhinal cortex

The hippocampus is well-known to be critical for trace fear conditioning, but nothing is known about the importance of perirhinal cortex (PR), which has reciprocal connections with hippocampus. PR damage severely impairs delay fear conditioning to ultrasonic vocalizations (USVs) and discontinuous tones (pips), but has no effect on delay conditioning to continuous tones. Here we demonstrate that trace auditory fear conditioning also critically depends on PR function. The trace interval between the CS offset and the US onset was 16 s. Pre-training neurotoxic lesions were produced through multiple injections of N-methyl- d-aspartate along the full length of PR, which was directly visualized during the injections. Control animals received injections with phosphate-buffered saline. Three-dimensional reconstructions of the lesion volumes demonstrated that the neurotoxic damage was well-localized to PR and included most of its anterior–posterior extent. Automated video analysis quantified freezing behavior, which served as the conditional response. PR-damaged rats were profoundly impaired in trace conditioning to either of three different CSs (a USV, tone pips, and a continuous tone) as well as conditioning to the training context. Within both the lesion and control groups, the type of cue had no effect on the mean CR. The overall PR lesion effect size was 2.7 for cue conditioning and 3.9 for context conditioning. We suggest that the role of PR in trace fear conditioning may be distinct from some of its more perceptual functions. The results further define the essential circuitry underlying trace fear conditioning to auditory cues.

Differential contribution of dorsal and ventral hippocampus to trace and delay fear conditioning

Trace conditioning relies on the maintained representation of a stimulus across a trace interval, and may involve a persistent trace of the conditioned stimulus (CS) and/or a contribution of contextual conditioning. The role of hippocampal structures in these two types of conditioning was studied by means of pretraining lesions and reversible inactivation of the hippocampus in rats. Similar levels of conditioning to a tone CS and to the context were obtained with a trace interval of 30 s. Neurotoxic lesions of the whole hippocampus or reversible muscimol inactivation of the ventral hippocampus impaired both contextual and tone freezing in both trace- and delay-conditioned rats. Dorsal hippocampal injections impaired contextual freezing and trace conditioning, but not delay conditioning. No dissociation between trace and contextual conditioning was observed under any of these conditions. Altogether, these data indicate that the ventral and dorsal parts of the hippocampus compute different aspects of trace conditioning, with the ventral hippocampus being involved in fear and anxiety processes, and the dorsal hippocampus in the temporal and contextual aspects of event representation.

Perirhinal cortex lesions produce retrograde amnesia for spatial information in rats: Consolidation or retrieval?

Several lines of evidence in humans and experimental animals suggest that the hippocampus is critical for the formation and retrieval of spatial memory. However, although the hippocampus is reciprocally connected to adjacent cortices within the medial temporal lobe and they, in turn, are connected to the neocortex, little is known regarding the function of these cortices in memory. Here, using a reference spatial memory task in the radial maze, we show that neurotoxic perirhinal cortex lesions produce a profound retrograde amnesia when learning-surgery intervals of 1 or 50 d are used (Experiment 1). With the aim of dissociating between consolidation and retrieval processes, we injected lidocaine either daily after training (Experiment 2) or before a retention test once the learning had been completed (Experiment 3). Results show that reversible perirhinal inactivation impairs retrieval but not consolidation. However, the same procedure followed in Experiment 2 disrupted consolidation when the lidocaine was injected into the dorsal hippocampus. The results of Experiment 4 rule out the possibility that the deficit in retrieval is due to a state-dependent effect. These findings demonstrate the differential contribution of various regions of the medial temporal lobe to memory, suggesting that the perirhinal cortex plays a key role in the retrieval of spatial information for a long period of time.

Lesions of the entorhinal cortex or fornix disrupt the context-dependence of fear extinction in rats

Recent studies have shown that the hippocampus is critical for the context-dependent expression of extinguished fear memories. Here we used Pavlovian fear conditioning in rats to explore whether the entorhinal cortex and fornix, which are the major cortical and subcortical interfaces of the hippocampus, are also involved in the context-dependence of extinction. After pairing an auditory conditional stimulus (CS) with an aversive footshock (unconditional stimulus or US) in one context, rats received an extinction session in which the CS was presented without the US in another context. Conditional fear to the CS was then tested in either the extinction context or a third familiar context; freezing behavior served as the index of fear. Sham-operated rats exhibited little conditional freezing to the CS in the extinction context, but showed a robust renewal of fear when tested outside of the extinction context. In contrast, rats with neurotoxic lesions in the entorhinal cortex or electrolytic lesions in the fornix did not exhibit a renewal of fear when tested outside the extinction context. Impairments in freezing behavior to the auditory CS were not able to account for the observed results, insofar as rats with either entorhinal cortex or fornix lesions exhibited normal freezing behavior during the conditioning session. Thus, contextual memory retrieval requires not only the hippocampus proper, but also its cortical and subcortical interfaces.

Glial Loss in the Prefrontal Cortex Is Sufficient to Induce Depressive-like Behaviors

Postmortem studies have repeatedly found decreased density and number of glia in cortical regions, including the prefrontal and cingulate areas, from depressed patients. However, it is unclear whether this glial loss plays a direct role in the expression of depressive symptoms. To address this question, we characterized the effects of pharmacologic glial ablation in the prefrontal cortex (PFC) of adult rats on behavioral tests known to be affected by stress or antidepressant treatments: sucrose preference test (SPT), novelty suppressed feeding test (NSFT), forced swim test (FST), and two-way active avoidance test (AAT). We established the dose and time course for the actions of an astrocyte specific toxin, L-alpha-aminoadipic acid (L-AAA), and compared the behavioral effects of this gliotoxin with the effects of an excitotoxic (ibotenate) lesion and to the effects of chronic stress. The results demonstrate that L-AAA infusions induced anhedonia in SPT, anxiety in NSFT, and helplessness in FST and AAT. These effects of L-AAA were similar to chronic unpredictable stress (CUS)-induced depressive-like behaviors in these tests. However, ibotenate-induced neurotoxic lesion of the PFC had no effect in these behavioral tests. The results demonstrate that glial ablation in the PFC is sufficient to induce depressive-like behaviors similar to chronic stress and support the hypothesis that loss of glia contributes to the core symptoms of depression.

Value in Development of a TAPIR-Like Mouse Monoclonal Antibody to Aβ

Value in Development of a TAPIR-Like Mouse Monoclonal Antibody to Aβ

Intact intracortical microstimulation (ICMS) representations of rostral and caudal forelimb areas in rats with quinolinic acid lesions of the medial or lateral caudate-putamen in an animal model of Huntington's disease

Neurotoxic, cell-specific lesions of the rat caudate-putamen (CPu) have been proposed as a model of human Huntington's disease and as such impair performance on many motor tasks, including skilled forelimbs tasks such as reaching for food. Because the CPu and motor cortex share reciprocal connections, it has been proposed that the motor deficits are due in part to a secondary disruption of motor cortex. The purpose of the present study was to examine the functionality of the motor cortex using intracortical microstimulation (ICMS) following neurotoxic lesions of the CPu. ICMS maps have been shown to be sensitive indicators of motor skill, cortical injury, learning, and experience. Long-evans hooded rats received a sham, a medial, or a lateral CPu lesion using the neurotoxin, quinolinic acid (2,3-pyridinedicarboxylic acid). Two weeks later the motor cortex was stimulated under light ketamine anesthesia. Neither lateral nor medial lesions of the CPu altered the stimulation threshold for eliciting forelimb movements, the type of movements elicited, or the size of the rostral forelimb (RFA) and caudal forelimb areas (CFA) from which movements were elicited. The preservation of ICMS forelimb movement representations (the forelimb map) in rats with cell-specific CPu lesions suggests motor impairments following lesions of the lateral striatum are not due to the disruption of the motor map. Therefore, the impairments that follow striatal cell loss are due either to alterations in circuitry that is independent of motor cortex or to alterations in circuitry afferent to the motor cortex projections.