Biomedical subjects

Matthew R Holahan

Publications and source records attributed to Matthew R Holahan.

13 recordsLinked to original sources

PubMed2007

Expansion and retraction of hippocampal mossy fibers during postweaning development: strain-specific effects of NMDA receptor blockade.

We have recently discovered differences in the distribution of the mossy fiber terminal field (MFTF) between adult Long-Evans rats (LER) and Wistar rats(WR): the suprapyramidal MFTF extends into distal stratum oriens (dSO) in LER, but is nearly absent in WR (Holahan et al.,2006, Hippocampus 16:560-570). To our knowledge, there is no developmental evidence that sheds light on how this strain-dependent MFTF innervation in the adult is achieved. Accordingly, the present study examined the time course of MFTF development from postnatal days 0 to 40 and the effect of NMDA-receptor antagonist 3-(2-carboxypiperazin-4-yl) propyl-1-phosphonic acid (CPP) on this developmental organization. In both LER and WR, a MFTF projection to dSO was observed between P18 and P21. By P24, the dSO projection in WR was no longer detectable whereas in LER, the dSO projection seen on P21 remained. We suggest that in WR a retraction of the MFTF projection from dSO to stratum lucidum between P21 and P24 leads to its adult pattern. In WR, CPP administration enhanced the dSO projection, possibly by blocking the retraction process. In LER, CPP administration reduced the dSO projection. Thus, in each strain, NMDA receptor blockade effectively reversed the developmental course of MFTF pattern of innervation. The present results lend strong support to the view that NMDA receptor regulation of input-dependent processes during development is of critical importance in promoting the motility and target selection of presynaptic MF axons. This regulation extends later into development than had previously been thought.

Age Factors↗

PubMed2007

Post-translational synaptic protein modification as substrate for long-lasting, remote memory: an initial test.

The current view of the molecular basis for information storage is that post-translational modification (PTM) of brain proteins is important for the early stages of memory storage and that protein synthesis is necessary for long-lasting memory. This view has been challenged by the proposal that PTM of synaptic proteins is the critical instructive mechanism underlying both recent as well as long-lasting memories (Routtenberg and Rekart, 2005). As an initial test, a broad spectrum serine/threonine kinase inhibitor (H-7) was delivered bilaterally to rat anterior cingulate cortex 1 h before a 3 week retention test of contextual fear conditioning. This significantly blocked 21-Day retention. In the second experiment evaluating extinction of a 21-Day remote memory, H-7 injected into mouse medial prefrontal cortex blocked fear extinction. As the H-7-induced impairment in 21-Day retention was indexed by a decrease in freezing, while the extinction blockade by no decrease in freezing, the results could not be ascribed to a direct effect of the drug on behavioral performance. This represents the first demonstration, to our knowledge, that PTM inhibition, here serine/threonine kinase activity, interferes with long-lasting memory, providing initial support for the PTM model.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗

PubMed2006

Spatial learning induces presynaptic structural remodeling in the hippocampal mossy fiber system of two rat strains.

Hebb (1949) proposed that after learning both presynaptic and postsynaptic structural changes form the neural substrate of long-lasting memory. Despite this, there are few instances linking presynaptic remodeling with learning. Here the authors demonstrate in two different rat strains that learning the location of a hidden platform induces expansion of the presynaptic hippocampal mossy fiber terminal field (MFTF) from the stratum lucidum to the distal stratum oriens (dSO). Prior to any training, Long Evans rats (LER) showed an extensive endogenous MFTF innervation of DSO, in contrast to Wistar rats (WR) that showed minimal innervation. LER showed better recall than WR on the hidden platform water maze task and a visible reversal water maze task. In both strains, significant MFTF expansion to dSO, spanning approximately 200 mum, was detected 7 days after training on the hidden platform task, but only LER showed significant MFTF expansion 24 h after training. It is attractive to think that the MFTF expansion to dSO contributes both to long-lasting memory formation and to facilitating spatial navigation strategies. The present results establish learning-induced axonal remodeling of the hippocampal MF system in adult rats as an especially useful system for exploring presynaptic morphological adjustments consequent to learning.

Animals↗

PubMed2005

Post-training intra-amygdala amphetamine injections given during acquisition of a stimulus-response (S-R) habit task enhance the expression of stimulus-reward learning: further evidence for incidental amygdala learning.

The effect of post-training intra-amygdala amphetamine injections was examined on the acquisition and expression of a visual discrimination task. Rats were trained to enter four lit arms for food (stimulus-response) and avoid unlit arms on an eight-arm radial maze visual discrimination task. Post-training intra-amygdala amphetamine injections (10 microg) were given for 4 consecutive days during the mid-point of training (days 20-23). The number of lit arm entries was used as a measure of stimulus-response habit learning 24 h after each injection. Twenty-four hours after the last injection, a transfer test was run to assess the effect of the same post-training manipulation. This transfer test assessed the amount of time spent in the lit arms and was used as a measure of stimulus-reward learning. Compared to saline-injected rats, rats that received post-training amphetamine spent more time in lit as opposed to dark arms during the transfer test. This occurred in the absence of an increase in the number of correct arm entries during visual discrimination training. This suggests that post-training amphetamine strengthened a stimulus-reward association that did not immediately affect behavioral output. This association may reflect a mnemonic representation stored in an ensemble of amygdala neurons.

Amphetamine↗

PubMed2005

Complementary roles for the amygdala and hippocampus during different phases of appetitive information processing.

Evidence collected from rodent models of memory storage suggests that rapid forms of learning engage the involvement of multiple brain regions each of which may participate in a different component of information processing. The present study used temporary inactivation of the amygdala and hippocampus during different phases of information processing on a one-trial appetitive-conditioning task to examine how these two regions might participate in the storage of appetitive memories. Male Long Evans rats were chronically implanted into the amygdala or dorsal hippocampus and food deprived. Rats were trained on a radial maze conditioned cue preference task where training occurred in one 40-min session and testing took place 24 h later. The amygdala or hippocampus was inactivated separately with muscimol (50 ng/microl) injected immediately before or after training, or immediately before testing. Saline-injected rats displayed a conditioned preference by spending more time in the arm that previously contained food than in the arm that did not contain food. Muscimol injected into the amygdala before training or testing blocked the conditioned preference. Muscimol injected into the hippocampus immediately after training blocked the conditioned preference. These results suggest that the processing of memories may require multiple contributions from separate brain systems for at least short-term (24 h) storage. The resulting output from each system may converge on a similar downstream target to influence behavior.

Amygdala↗

PubMed2005

Impairment in long-term retention but not short-term performance on a water maze reversal task following hippocampal or mediodorsal striatal N-methyl-D-aspartate receptor blockade.

Male Long-Evans rats were injected with 32 ng/mul of the N-methyl-D-aspartate (NMDA) receptor antagonist 3-(2-carboxypiperazin-4-yl) propyl-1-phosphonic acid (CPP) or vehicle and trained to locate a hidden platform in a different location (reversal training) than used on the initial 4 days of training. Rats treated with vehicle or CPP into the dorsal hippocampus, basolateral amygdala, or mediodorsal striatum had similar latencies to locate the platform on the reversal day. Rats infused with CPP into the dorsal hippocampus or mediodorsal striatum failed to search preferentially in the novel location during a 24-hr, drug-free retention test, whereas all other groups searched preferentially in this location. Therefore, blocking dorsal hippocampal or mediodorsal striatal NMDA receptors selectively blocked long-term spatial retention without producing short-term performance deficits.

Analysis of Variance↗

PubMed2005

NMDA-receptor blockade by CPP impairs post-training consolidation of a rapidly acquired spatial representation in rat hippocampus.

Recent evidence suggests that N-methyl-D-aspartate (NMDA)-receptor mediated plasticity in hippocampus has a more subtle role in memory-based behaviours than originally thought. One idea is that NMDA-based plasticity is essential for the consolidation of post-training memory but not for the initial encoding or for short-term memory. To further test this idea we used a three-phase variant of the hidden goal water maze task. In the first phase, rats were pre-trained to an initial location. Next, intense, massed training was done in a 2-h interval to teach the rats to go to a new location after either an injection of the NMDA receptor antagonist (6)-3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid (CPP) or of vehicle. Finally, under drug-free conditions 24 h after new location training, a competition test was done between the original and new locations. We find that N-methyl-D-aspartate (NMDA)-receptor blockade has little or no effect on new location training. In contrast, when tested 24 h later, the strength of the trace for the new location learned during NMDA-receptor blockade was much weaker compared with the trace for the new location learned after saline injection. Further experiments showed similar effects when NMDA-receptors were blocked immediately after the new location training, suggesting that this is a memory consolidation effect. Our results therefore reinforce the notion that hippocampal NMDA-receptors participate in post-training memory consolidation but are not essential for the processes necessary to learn or retain navigational information in the short term.

Animals↗

PubMed2004

Intra-amygdala muscimol injections impair freezing and place avoidance in aversive contextual conditioning.

Rats were trained by shocking them in a closed compartment. When subsequently tested in the same closed compartment with no shock, normal rats showed an increased tendency to freeze. They also showed an increased tendency to actively avoid the compartment when given access to an adjacent neutral compartment for the first time. Amygdala inactivation with bilateral muscimol injections before training attenuated freezing and eliminated avoidance during the test. Rats trained in a normal state and given intra-amygdala muscimol injections before the test did not freeze or avoid the shock-paired compartment. This pattern of effects suggests that amygdala inactivation during training impaired acquisition of a conditioned response (CR) due either to inactivation of a neural substrate essential for its storage or to elimination of a memory modulation effect that facilitates its storage in some other brain region(s). The elimination of both freezing and active avoidance by amygdala inactivation during testing suggests that neither of these behaviors is the CR. The possibility that the CR is a set of internal responses that produces both freezing and avoidance as well as other behavioral effects is discussed.

Amygdala↗

PubMed2004

Amygdala c-Fos induction corresponds to unconditioned and conditioned aversive stimuli but not to freezing.

These experiments examined the relationship between freezing and c-Fos expression in the amygdala. In Experiment 1 freezing was elevated during a period immediately following shock in rats that remained in the shock context, but not in rats that were moved to a different, neutral context. The two groups showed equally elevated c-Fos levels in both the central (CeA) and lateral (LA) nuclei. In Experiment 2 rats were shocked in one compartment (paired) and not shocked in another, distinct compartment (unpaired). Rats re-exposed to the paired compartment 24h later froze more than rats exposed to the unpaired compartment, and rats in both groups froze more than un-shocked rats. c-Fos protein expression in CeA, LA and basolateral (BLA) nucleus was elevated in the rats exposed to the paired compartment but not in rats exposed to the unpaired compartment. Thus, c-Fos expression was induced by exposure to both unconditioned and conditioned stimuli, although it is unclear if the same cell population was activated in both cases. Neither case of c-Fos expression coincided with the occurrence of freezing. c-Fos expression may represent neural activity in LA and CeA produced by exposure to unconditioned cues and activity in BLA, LA and CeA produced by conditioned cues. This activity may contribute to an aversive affective state (or "fear"). Behaviors promoted by this state, such as freezing, may be mediated in other brain areas, or by other neurons in the amygdala.

Acetylcholinesterase↗

PubMed2004

Amygdala inactivation blocks expression of conditioned memory modulation and the promotion of avoidance and freezing.

Rats were exposed to shock-paired cues immediately after training on an appetitive preference task. Elevated levels of freezing in and active avoidance of the shock-paired compartment were observed, and memory for the appetitive task was improved when tested 24 hr later. Intra-amygdala muscimol injected before the posttraining exposure eliminated freezing, avoidance, and memory modulation. The blockade of both freezing and active avoidance, which involve competing behavioral tendencies, makes it unlikely that the amygdala itself generates either behavior. The elimination of conditioned memory modulation suggests that conditioned neurohormonal responses were blocked. These conditioned internal responses may comprise the intervening variable of "conditioned fear" and may promote observable behaviors, the form of which is determined by the environment in which they occur.

Amygdala↗

PubMed2003

Involuntary, unreinforced (pure) spatial learning is impaired by fimbria-fornix but not by dorsal hippocampus lesions.

Pure spatial learning occurs when rats acquire information about an environment while exploring it in the absence of reinforcers. We previously reported that voluntary, unreinforced exploration of a radial maze retards subsequent reinforced conditioned cue preference (CCP) learning in the same maze. In the present experiment, we examined the effects of involuntary, unreinforced pre-exposure to a radial maze. During pre-exposure, rats were moved by an experimenter between the ends of two arms of a radial maze five times in 30 min. This form of pre-exposure retarded CCP learning, whereas rats that were not pre-exposed and rats that were pre-exposed to a maze in a different room displayed normal CCP learning. These findings suggest that some information specific to the maze environment was acquired during involuntary unreinforced pre-exposure to it. In experiment 2, the retardation of reinforced CCP learning by involuntary unreinforced pre-exposure was eliminated by fimbria-fornix lesions made before pre-exposure but was unaffected by fimbria-fornix lesions made after pre-exposure but before training. Large neurotoxic lesions of the dorsal hippocampus made before pre-exposure had no effect on the retardation of CCP learning, but the rats with these lesions were impaired on a standard test of reinforced spatial learning in a water maze. The lesion effects in experiment 2 are similar to those previously reported for voluntary exploration and suggest that pure spatial learning may occur during both voluntary exploration of and involuntary exposure to an environment in the absence of reinforcers. Pure spatial learning can apparently occur with exposure to two different locations within an environment, but the rats do not have to move between the locations voluntarily. An intact fimbria-fornix is required for acquisition but not expression of this form of learning. The hippocampus is not involved in this form of learning.

Animals↗

PubMed2002

Appetitive instrumental learning is impaired by inhibition of cAMP-dependent protein kinase within the nucleus accumbens.

The medium spiny neurons of the nucleus accumbens receive a unique convergence of dopaminergic and glutamatergic inputs from regions associated with motivational, cognitive, and sensory processes. Long-term forms of plasticity in the nucleus accumbens associated with such processes as appetitive learning and drug addiction may require coactivation of both dopamine D1 and glutamate N-methyl-D-aspartate (NMDA) receptors. This notion implies that an intracellular mechanism is likely to be involved in these long-term neuroadaptive processes. The present series of experiments examined the effects of intra-accumbens microinfusion of protein kinase inhibitors on acquisition of an instrumental task, lever-pressing for food. Male Sprague-Dawley rats were bilaterally implanted with chronic indwelling cannulae aimed at the nucleus accumbens core. Following recovery, animals were food-restricted and subsequently trained for operant responding. The broad-based serine/threonine kinase inhibitor H-7 (5 or 27 nmol per side) dose-dependently impaired learning when infused immediately after testing on days 1-4. Rp-cAMPS, a cAMP-dependent protein kinase (PKA) inhibitor, also impaired learning regardless of whether it was infused immediately before (5 or 20 nmol) or immediately after (10 nmol) testing on days 1-4. Rp-cAMPS (10 nmol) also inhibited learning when infused 1 h after testing, though to a lesser extent than when administered before or immediately after testing. The PKA stimulator Sp-cAMPS (5 or 20 nmol) also impaired learning when infused before testing, suggesting that there is an optimal level of PKA activity required for learning. None of the drugs used produced nonspecific motor or feeding effects. These results provide evidence supporting the involvement of nucleus accumbens PKA in appetitive learning and suggest that this kinase may be involved in long-term changes associated with this and other motivationally based neuroadaptive processes.

Animals↗

PubMed2002

Conditioned memory modulation, freezing, and avoidance as measures of amygdala-mediated conditioned fear.

Three conditioned aversive responses were used to infer the existence of an unobservable central state of "conditioned fear," and the roles of certain amygdala subregions in producing these responses were investigated. Rats received tone-shock pairings in one compartment of a shuttle box and no tones or shocks in the other, distinctive, compartment. They were then trained to find food in one arm of a Y-maze. After the final training trial they were exposed to different sets of stimuli in the shuttle box with no shock. Twenty-four hours later rats that had received immediate posttraining exposure to the conditioned stimuli (in the shock-paired compartment) made significantly more correct responses on the Y-maze than rats that had been exposed to the neutral stimuli (in the no-shock compartment) or rats that had received delayed posttraining exposure to the conditioned stimuli. This constitutes a demonstration of posttraining memory modulation by conditioned aversive stimuli. Freezing increased during posttraining exposure to the conditioned stimuli compared to the neutral stimuli. When subsequently allowed to move freely between the two compartments, the rats in all groups also showed significant conditioned avoidance of the compartment containing the conditioned stimuli. In a second experiment the effects of lesions confined to specific parts of the amygdala on the three conditioned responses (memory modulation, freezing, avoidance) were tested. Lesions of the central nucleus impaired all three conditioned responses; lesions of the medial nucleus impaired conditioned modulation and avoidance. These lesions had no effect on freezing during the training trials. Lesions of the lateral and basolateral nuclei attenuated freezing during both training and testing. The findings suggest that the central and medial nuclei of the amygdala may be important parts of neural circuits mediating conditioned responses that constitute conditioned aversive states, but that conditioned freezing may be mediated independently.

Acoustic Stimulation↗