Form Of Neural Plasticity Research Articles

Relating Cortical Wave Dynamics to Learning and Remembering

Electrical waves propagate across sensory and motor cortices in stereotypical patterns. These waves have been described as potentially facilitating sensory processing when they travel through sensory cortex, as guiding movement preparation and performance when they travel across motor cortex, and as possibly promoting synaptic plasticity and the consolidation of memory traces, especially during sleep. Here, an alternative theoretical framework is suggested that integrates Pavlovian hypotheses about learning and cortical function with concepts from contemporary proceduralist theories of memory. The proposed framework postulates that sensory-evoked cortical waves are gradually modified across repeated experiences such that the waves more effectively differentiate sensory events, and so that the waves are more likely to reverberate. It is argued that the qualities of cortical waves—their origins, form, intensity, speed, periodicity, extent, and trajectories —are a function of both the structural organization of neural circuits and ongoing reverberations resulting from previously experienced events. It is hypothesized that experience-dependent cortical plasticity, both in the short- and long-term, modulates the qualities of cortical waves, thereby enabling individuals to make progressively more precise distinctions between complex sensory events, and to reconstruct components of previously experienced events. Unlike most current neurobiological theories of learning and memory mechanisms, this hypothesis does not assume that synaptic plasticity, or any other form of neural plasticity, serves to store physical records of previously experienced events for later reactivation. Rather, the reorganization of cortical circuits may alter the potential for certain wave patterns to arise and persist. Understanding what factors determine the spatiotemporal dynamics of cortical waves, how structural changes affect their qualities, and how wave dynamics relate to both mental experiences and memory-based performances, may provide new insights into the nature of learning and memory.

The Role of Dentate Gyrus Neurogenesis in Neuropsychiatric Disorders

The Role of Dentate Gyrus Neurogenesis in Neuropsychiatric Disorders

Decreasing temperature shifts hippocampal function from memory formation to modulation of hibernation bout duration in Syrian hamsters

Previous studies in hibernating species have characterized two forms of neural plasticity in the hippocampus, long-term potentiation (LTP) and its reversal, depotentiation, but not de novo long-term depression (LTD), which is also associated with memory formation. Studies have also shown that histamine injected into the hippocampus prolonged hibernation bout duration. However, spillover into the ventricles may have affected brain stem regions, not the hippocampus. Here, we tested the hypothesis that decreased brain temperature shifts the major function of the hippocampus in the Syrian hamster (Mesocricetus auratus) from one of memory formation (via LTP, depotentiation, and de novo LTD) to increasing hibernation bout duration. We found reduced evoked responses in hippocampal CA1 pyramidal neurons following low-frequency stimulation in young (<30 days old) and adult (>60 days old) hamsters, indicating that de novo LTD was generated in hippocampal slices from both pups and adults at temperatures >20°C. However, at temperatures below 20°C, synchronization of neural assemblies (a requirement for LTD generation) was markedly degraded, implying that de novo LTD cannot be generated in hibernating hamsters. Nonetheless, even at temperatures below 16°C, pyramidal neurons could still generate action potentials that may traverse a neural pathway, suppressing the ascending arousal system (ARS). In addition, histamine increased the excitability of these pyramidal cells. Taken together, these findings are consistent with the hypothesis that hippocampal circuits remain operational at low brain temperatures in Syrian hamsters and suppress the ARS to prolong bout duration, even though memory formation is muted at these low temperatures.

Roles of a Novel Molecule &amp;#x2018;Shati&amp;#x2019; in the Development of Methamphetamine-Induced Dependence

The ability of drugs of abuse to cause dependence can be viewed as a form of neural plasticity. Recently, we have demonstrated that tumor necrosis factor-α (TNF-α) increases dopamine uptake and inhibits methamphetamine-induced dependence. Moreover, we have identified a novel molecule ‘shati’ in the nucleus accumbens of mice treated with methamphetamine using the PCR-select cDNA subtraction method and clarified that it is involved in the development of methamphetamine dependence: Treatment with the shati antisense oligonucleotide (shati-AS), which inhibits the expression of shati mRNA, enhanced the methamphetamine-induced hyperlocomotion, sensitization, and conditioned place preference. Further, blockage of shati mRNA by shati-AS potentiated the methamphetamine-induced increase of dopamine overflow and the methamphetamine-induced decrease in dopamine uptake in the nucleus accumbens. Interestingly, treatment with shati-AS also inhibited expression of TNF-α. Transfection of the vector containing shati cDNA into PC12 cells, dramatically induced the expression of shati and TNF-α mRNA, accelerated dopamine uptake, and inhibited the methamphetamine-induced decrease in dopamine uptake. These effects were blocked by neutralizing TNF-α. These results suggest that the functional roles of shati in methamphetamine-induced behavioral changes are mediated through the induction of TNF-α expression which inhibits the methamphetamine-induced increase of dopamine overflow and decrease in dopamine uptake.

The role of high-level visual areas in short- and long-lasting forms of neural plasticity

The role of high-level visual areas in short- and long-lasting forms of neural plasticity

Fibroblast growth factor-1 within the ventral tegmental area participates in motor sensitizing effects of morphine

Drug addiction is viewed as a form of neural plasticity, and neurotrophic factors have been implicated in many forms of plasticity in the adult nervous system. Here we show that the fibroblast growth factor-1 (FGF-1), that is expressed on dopamine and GABA neurons of the ventral tegmental area (VTA), is involved in the sensitizing effects of morphine. The receptor FGFR-1 is expressed on VTA astrocytes, as well as dopamine and GABA neurons. FGF-1 or anti-FGF-1 infusions into the VTA during the induction (not expression) phase of sensitization advanced or blocked morphine's activating motor effects respectively, in a dose–dependent manner. Infusions into the adjacent substantia nigra, whose neurons also express FGF-1 and FGFR-1, did not modify normal morphine-induced sensitization. Biochemical traits related to morphine's sensitizing effects were altered by intra-VTA anti-FGF-1 because morphine-induced upregulation of both tyrosine hydroxylase (TH) and N-methyl d-aspartate glutamate receptor 1 (NMDAR1) in the VTA was blocked after anti-FGF-1. Changes in the activation state of VTA calcium/calmodulin-dependent kinase type II seem to participate in FGF-1-induced effects as well. We conclude that the FGF-1 system of the ventral tegmental area is required for biochemical and behavioral sensitization to this drug.

Recovery of motor and cognitive function after cerebellar lesions in a songbird – role of estrogens

In addition to its key role in complex motor function, the cerebellum is increasingly recognized to have a role in cognition. Songbirds are particularly good models for the investigation of motor and cognitive processes but little is known about the role of the songbird cerebellum in these processes. To explore cerebellar function in a songbird, we lesioned the cerebellum of adult female zebra finches and examined the effects on a spatial working memory task and on motor function during this task. There is evidence for steroid synthesis in the songbird brain and neurosteroids may have an impact on some forms of neural plasticity in adult songbirds. We therefore hypothesized that neurosteroids would affect motor and cognitive function after a cerebellar injury. We found that cerebellar lesions produced deficits in motor and cognitive aspects of a spatial task. In line with our prediction, birds in which estrogen synthesis was blocked had impaired performance in our spatial task compared with those that had estrogen synthesis blocked but estrogen replaced. There was no clear effect of estrogen replacement on motor function. We also found that lesions induced expression of the estrogen synthetic enzyme aromatase in reactive astrocytes and Bergmann glia around a cerebellar lesion. These data suggest that the cerebellum of songbirds mediates both motor and cognitive function and that estrogens may improve the recovery of cognitive aspects of cerebellar function after injury.

Downregulation of tonic GABA currents following epileptogenic stimulation of rat hippocampal cultures

Deficits in GABAergic inhibitory transmission are a hallmark of temporal lobe epilepsy and have been replicated in animal and tissue culture models of epilepsy. GABAergic inhibition comprises phasic and tonic inhibition that is mediated by synaptic and extrasynaptic GABAA receptors, respectively. We have recently demonstrated that chronic stimulation with cyclothiazide (CTZ) or kainic acid (KA) induces robust epileptiform activity in hippocampal neurons both in vitro and in vivo. Here, we report a downregulation of tonic GABA inhibition after chronic epileptogenic stimulation of rat hippocampal cultures. Chronic pretreatment of hippocampal neurons with CTZ or KA resulted in a marked reduction in GABAergic inhibition, as shown by a significant decrease in whole-cell GABA currents and in the frequency of miniature inhibitory postsynaptic currents (mIPSCs). Interestingly, synaptically localized GABAA receptors remained relatively stable, as evidenced by the unaltered amplitude of mIPSCs, as well as the unchanged punctate immunoreactivity of gamma2 subunit-containing postsynaptic GABAA receptors. In contrast, tonic GABA currents, assessed either by a GABAA receptor antagonist bicuculline or a selective extrasynaptic GABAA receptor agonist THIP, were significantly reduced following epileptogenic stimulation. These results reveal a novel form of neural plasticity, that epileptogenic stimulation can selectively downregulate extrasynaptic GABAA receptors while leaving synaptic GABAA receptors unchanged. Thus, in addition to synaptic alteration of GABAergic transmission, regulation of tonic inhibition may also play an important role during epileptogenesis.

Synaptic Incorporation of AMPA Receptors during LTP Is Controlled by a PKC Phosphorylation Site on GluR1

Incorporation of GluR1-containing AMPA receptors into synapses is essential to several forms of neural plasticity, including long-term potentiation (LTP). Numerous signaling pathways that trigger this process have been identified, but the direct modifications of GluR1 that control its incorporation into synapses are unclear. Here, we show that phosphorylation of GluR1 by PKC at a highly conserved serine 818 residue is increased during LTP and critical for LTP expression. GluR1 is phosphorylated by PKC at this site in vitro and in vivo. In addition, acute phosphorylation at GluR1 S818 by PKC, as well as a phosphomimetic mutation, promotes GluR1 synaptic incorporation. Conversely, preventing GluR1 S818 phosphorylation reduces LTP and blocks PKC-driven synaptic incorporation of GluR1. We conclude that the phosphorylation of GluR1 S818 by PKC is a critical event in the plasticity-driven synaptic incorporation of AMPA receptors.

GAP‐43 heterozygous mice show delayed barrel patterning, differentiation of radial glia, and downregulation of GAP‐43

GAP-43 heterozygous (HZ) mice exhibit abnormal thalamocortical pathfinding, fasciculation, and terminal arborization at postnatal day 7 (P7). Here we tested whether these defects are correlated with delayed development of HZ cortical patterns. We assessed the rate of barrel segregation and radial glia differentiation in wild-type (WT) and HZ cortices. Since GAP-43 is involved in some forms of neural plasticity, we also compared the duration of the critical period for lesion-induced plasticity in both genotypes. Cytochrome oxidase histochemistry revealed a delay of approximately 1 day in barrel pattern formation in GAP-43 HZ mice. GAP-43 WT barrels showed complete segregation between P2-P3, while HZ barrels did not reach the same level of segregation until P3-P4. We found a similar delay in the transformation of radial glia from monopolar to multipolar phenotypes, from P5 in WT to P7 in HZ cortex. Radial glial cells represent many of the neuronal progenitors in developing cortex and aid in cell migration. Thus, the delay in radial glial differentiation may contribute to the delay in HZ barrel segregation. Interestingly, we found no change in the extent of the critical period for HZ cortical responsiveness to early peripheral damage or in the time course of the cortical response. As expected, GAP-43 expression in HZ cortex is significantly reduced early in development. However, HZ GAP-43 expression remains at maximum levels after P9, when it is normally downregulated. As a result, HZ GAP-43 expression is near-normal by P26, by which time near-normal barrel dimensions have been restored. Our findings indicate that GAP-43 deficiency leads to early delays in barrel development and suggest that these failures are followed by homeostatic responses, including prolonged GAP-43 expression. These compensatory mechanisms may rescue normal cortical reorganization in neonates and near-normal barrel morphology and GAP-43 expression in adulthood.

Adenylyl cyclase type-VIII activity is regulated by G βγ subunits

The Ca 2+-activated adenylyl cyclase type VIII (AC-VIII) has been implicated in several forms of neural plasticity, including drug addiction and learning and memory. It has not been clear whether G i/o proteins and G-protein coupled receptors regulate the activity of AC-VIII. Here we show in intact mammalian cell system that AC-VIII is inhibited by μ-opioid receptor activation and that this inhibition is pertussis toxin sensitive. Moreover, we show that G βγ subunits inhibit AC-VIII activity, while constitutively active α i/o subunits do not. Different G β isoforms varied in their efficacies, with G β1γ2 or G β2γ2 being more efficient than G β3γ2 and G β4γ2, while G β5 (transfected with γ 2) had no effect. As for the G γ subunits, G β1 inhibited AC-VIII activity in the presence of all γ subunits tested except for γ 5 that had only a marginal activity. Moreover, cotransfection with proteins known to serve as scavengers of G βγ dimers, or to reduce G βγ plasma membrane anchorage, markedly attenuated the μ-opioid receptor-induced inhibition of AC-VIII. These results demonstrate that G βγ (originating from agonist activation of these receptors) and probably not G αi/o subunits are involved in the agonist inhibition of AC-VIII.

Tinnitus as a plastic phenomenon and its possible neural underpinnings in the dorsal cochlear nucleus

Tinnitus displays many features suggestive of plastic changes in the nervous system. These can be categorized based on the types of manipulations that induce them. We have categorized the various forms of plasticity that characterize tinnitus and searched for their neural underpinnings in the dorsal cochlear nucleus (DCN). This structure has been implicated as a possible site for the generation of tinnitus-producing signals owing to its tendency to become hyperactive following exposure to tinnitus inducing agents such as intense sound and cisplatin. In this paper, we review the many forms of plasticity that have been uncovered in anatomical, physiological and neurochemical studies of the DCN. Some of these plastic changes have been observed as consequences of peripheral injury or as fluctuations in the behavior and chemical activities of DCN neurons, while others can be induced by stimulation of auditory or even non-auditory structures. We show that many parallels can be drawn between the various forms of plasticity displayed by tinnitus and the various forms of neural plasticity which have been defined in the DCN. These parallels lend further support to the hypothesis that the DCN is an important site for the generation and modulation of tinnitus-producing signals.

The Cerebellum Modulates Rodent Cortical Motor Output after Repetitive Somatosensory Stimulation

To analyze the possible role of the cerebellum in the modulation of cortical motor output associated with repetitive electrical stimulation of the sciatic nerve in the rat. A sustained somatosensory stimulation induces an increase in the intensity of the response of the rodent motor cortex. Wistar rats were anesthetized for surgical preparation using a continuous infusion of chloral hydrate. We analyzed the response evoked by electrical stimulation of the right motor cortex before (basal condition) and after peripheral electrical stimulation of the left sciatic nerve in rats with no cerebellar intervention (n = 6), and in control rats with Ringer's infusion via a microdialysis probe (n = 8) implanted in the left cerebellar nuclei. In addition, we investigated the effects of 1) the administration of ethanol (20 mmol/L) in the left cerebellar nuclei (n = 5); 2) the administration of tetrodotoxin (10 micromol/L), a sodium channel blocker, in the left cerebellar nuclei (n = 5); 3) electrical stimulation by deep cerebellar stimulation (frequency 100 Hz) on the left side (n = 5); or 4) electrical stimulation of the cerebellar nuclei on the right side (100 Hz; n = 6). For peripheral stimulation, all of the animals received 1 hour of electrical stimulation. Trains of stimulation consisted of five stimuli (duration of 1 stimulus, 1 ms) at a rate of 10 Hz. During stimulation of the motor cortex, peak-to-peak amplitudes in responses of the left calf muscle were analyzed. Motor threshold was defined as the lowest intensity eliciting at least 5 of 10 evoked responses with an amplitude greater than 20 muV. The intensity used was 130% of the motor threshold. In the basal condition (before repetitive stimulation), amplitudes of motor responses were similar in the six groups of rats (P = 0.40). In rats without cerebellar intervention, peripheral electrical stimulation was associated with an increase of motor response to 147.4 +/- 8.5% of baseline (P < 0.001). In rats with Ringer's infusion, the motor response increased to 141.6 +/- 7.9% of baseline (P < 0.001). The administration of ethanol in the cerebellum prevented the enhancement of the response ipsilaterally. The mean +/- standard deviation (SD) of motor responses was 105.7 +/- 6.2% of baseline measurements after stimulation of the sciatic nerve (P = 0.36). The same observation was made after the infusion of tetrodotoxin (mean +/- SD of motor responses: 107.1 +/- 7.4% after peripheral stimulation [P = 0.19] and after electrical stimulation of the cerebellum on the left side [mean +/- SD of motor responses, 104.3 +/- 8.5% after peripheral stimulation, P = 0.40]). However, electrical stimulation of cerebellar nuclei on the right side did not impair the modulation of cortical motor output by sciatic nerve stimulation (mean +/- SD of motor responses, 148.4 +/- 5.8% after peripheral stimulation, P < 0.001). Until now, the increase of motor output after peripheral nerve stimulation has been considered as a plasticity directly and solely dependent on cortical structures. We demonstrate that the cerebellum plays a key role in this form of neural plasticity.

Song tutoring triggers CaMKII phosphorylation within a specialized portion of the avian basal ganglia

In several songbird species, a specialized anterior forebrain pathway (AFP) that includes part of the avian basal ganglia has been implicated specifically in song learning. To further elucidate cellular mechanisms and circuitry involved in vocal learning, we used quantitative immunoblot analysis to determine if early song tutoring promotes within the AFP phosphorylation of calcium/calmodulin-dependent kinase II (CaMKII), a multifunctional kinase whose phosphorylation at threonine 286 is critical for many forms of neural plasticity and behavioral learning. We report that in young male zebra finches likely to have begun the process of song acquisition, brief tutoring by a familiar conspecific adult promotes a dramatic increase in levels of phosphorylated CaMKII (pCaMKII) in Area X, the striatal/pallidal component of the AFP. In contrast, pCaMKII levels in this region were not elevated if 1) the tutor did not sing, 2) the tutor sang but was visually isolated from the pupil, or 3) the tutor was an unfamiliar adult. In young males that had not previously heard any conspecific song, first exposure to a song tutor produced a more modest, but significant rise in pCaMKII levels. Young females (who do not develop song behavior) did not exhibit any effect of tutoring on pCaMKII levels in that portion of the basal ganglia that corresponds to Area X in males. These data are consistent with the hypothesis that Area X participates in encoding and/or attaching reward value to a representation of tutor song that is accessed later to guide motor learning.

Acute injections of brain-derived neurotrophic factor in a vocal premotor nucleus reversibly disrupt adult birdsong stability and trigger syllable deletion

Behavioral variability serves an essential role in motor learning by enabling sensory feedback to select those motor patterns that minimize error. Birds use auditory feedback to learn how to sing, and their songs lose variability and become highly stereotyped, or crystallized, at the end of a sensitive period for sensorimotor learning. The molecular cues that regulate song variability are not well understood. In other systems, neurotrophins, and brain-derived neurotrophic factor (BDNF) in particular, can mediate various forms of neural plasticity, including sensitive period neural circuit plasticity and activity-dependent synapse formation, and may also influence learning and memory. Here, we have tested the hypothesis that neurotrophin expression in the robust nucleus of the arcopallium (RA), the telencephalic output controlling song, regulates song variability. BDNF and its receptor trkB are expressed in RA, and BDNF expression in RA appears to be highest in juveniles, when song is most variable and plastic, and synapse density highest. Thus, song variability and synaptic connectivity could be enhanced by augmented expression of BDNF in RA. In support of this idea, we found that BDNF injections into the adult RA induced the re-expression of juvenile-like phenotypes, including song variability and an increased synaptic density in RA. Furthermore, BDNF treatment also induced vocal plasticity, characterized by syllable deletions and persistent changes to the song patterns. These results suggest that endogenous BDNF could be a molecular regulator of the song variability essential to vocal plasticity and, ultimately, to song learning.

Regulation of cellular plasticity and resilience by mood stabilizers: the role of AMPA receptor trafficking

There is increasing evidence from a variety of sources that severe mood disorders are associated with regional reductions in brain volume, as well as reductions in the number, size, and density of glia and neurons in discrete brain areas. Although the precise pathophysiology underlying these morphometric changes remains to be fully elucidated, the data suggest that severe mood disorders are associated with impairments of structural plasticity and cellular resilience. In this context, it is noteworthy that a growing body of data suggests that the glutamaiergic system (which is known to play a major role in neuronal plasticity and cellular resilience) may be involved in the pathophysiology and treatment of mood disorders. Glutamate α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) GluR1 receptor trafficking plays a critical role in regulating various forms of neural plasticity. It is thus noteworthy that recent studies have shown that structurally dissimilar mood stabilizers lithium and valproate regulate GluR1 receptor subunit trafficking and localization at synapses. These studies suggest that regulation of glutamatergically mediated synaptic plasticity may play a role in the treatment of mood disorders, and raises the possibility that agents more directly affecting synaptic GluR1 represent novel therapies for these devastating illnesses.

ERK regulation in chronic ethanol exposure and withdrawal

The extracellular signal regulated protein kinases (ERKs), also known as mitogen-activated protein kinases (MAPK) of 42 and 44 kd, play a crucial role in the induction of various forms of neural plasticity. Ethanol induces long-lasting functional changes that are more severe following repeated exposure and may involve intracellular signal transduction mechanisms. Therefore, we investigated the regulation of the ERK signal transduction pathway in models of continuous and intermittent ethanol exposure and withdrawal. Moderate blood alcohol levels (BALs) reduced ERK activation in most of the brain regions studied. Conversely, during withdrawal, activation of ERK was increased in most areas with some regional variations in the levels and kinetics of induction. The most dramatic effects were observed in the amygdala, the cerebellum, the striatum and the hippocampus. In the amygdala and the cerebellum, the activation of ERK observed during withdrawal was significantly higher after intermittent ethanol exposure than after continuous exposure, suggesting the establishment of a form of sensitization to the effects of withdrawal on ERK regulation. Thus the dysregulation of the ERK pathway could contribute to escalation of withdrawal symptoms induced by repeated withdrawal and possibly to the neuroadaptative changes believed to underlie progression towards addiction.

Post-training cyclooxygenase-2 (COX-2) inhibition impairs memory consolidation.

Evidence indicates that prostanoids, such as prostaglandins, play a regulatory role in several forms of neural plasticity, including long-term potentiation, a cellular model for certain forms of learning and memory. In these experiments, the significance of the COX isoforms cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) in post-training memory processes was assessed. Adult male Long-Evans rats underwent an eight-trial (30-sec intertrial interval) training session on a hippocampus-dependent (hidden platform) or dorsal striatal-dependent (visible platform) tasks in a water maze. After the completion of training, rats received an intraperitoneal injection of the nonselective COX inhibitor indomethacin, the COX-1-specific inhibitor piroxicam, the COX-2-specific inhibitor N-[2-cyclohexyloxy-4-nitrophenyl]-methanesulfonamide (NS-398), vehicle (45% 2-hydroxypropyl-beta-cyclodextrin in distilled water), or saline. On a two-trial retention test session 24 h later, latency to mount the escape platform was used as a measure of memory. In the hidden platform task, the retention test escape latencies of rats administered indomethacin (5 and 10 mg/kg) or NS-398 (2 and 5 mg/kg) were significantly higher than those of vehicle-treated rats, indicating an impairment in retention. Injections of indomethacin or NS-398 that were delayed 2 h post-training had no effect on retention. Post-training indomethacin or NS-398 had no influence on retention of the visible platform version of the water maze at any of the doses administered. Furthermore, selective inhibition of COX-1 via post-training piroxicam administration had no effect on retention of either task. These findings indicate that COX-2 is a required biochemical component mediating the consolidation of hippocampal-dependent memory.

Aging and synaptic plasticity: a review.

Aging affects all systems, but the brain seems to be particularly vulnerable to the action of negative, age-dependent factors. A gradual loss of memory functions is one of the earliest and most widespread consequences of brain aging. The causes for such impairment are still unclear. Long-term potentiation (LTP) is one form of neural plasticity, which has been proposed as the cellular correlate for memory. LTP is affected by aging, and such alteration might be causally related to memory dysfunction. In the present paper, we review the evidence sustaining the existence of a causal link between cognitive and LTP impairments, as well as the possible mechanisms involved. New results indicate a possible involvement of a deficient reinforcement of LTP by affective influences.

Memory consolidation in day-old chicks requires BDNF but not NGF or NT-3; an antisense study

Neurotrophins have been implicated in memory consolidation and recall as well as in other forms of neural plasticity. This study examined the effects of Brain-Derived Neurotrophic Factor (BDNF), Nerve Growth Factor (NGF) and Neurotrophin-3 (NT-3) on consolidation of memory for a one-trial passive avoidance task in day-old chicks. In this task chicks, having pecked once at a bitter tasting bead, avoid a similar but dry bead subsequently. Intracerebral administration of antisense ODNs to BDNF 6–12 h prior to training induced amnesia for the avoidance response by 3 h after training. Administration of a ‘control’ scrambled sequence or saline had no effect on recall; chicks continued to avoid the bead. Treatment with BDNF-AS did not inhibit shorter-term recall; amnesia was not present 1 h after training, but prevented longer-term recall, as amnesia was still present 24 h after training. Treatment with BDNF-antisense reduced both BDNF mRNA and BDNF protein in the chick brain, but did not alter mRNA levels of glyceraldehyde-3-phosphate dehydrogenase. By contrast, no effect of antisense to NGF or NT-3 on behaviour was observed, even though administration reduced the mRNA for each. There were no significant effects of any antisense on other behavioural measures at the doses used. Thus we conclude that BDNF has a specific role in memory consolidation for the passive avoidance task.