Biomedical subjects

Daniel A Nicholson

Publications and source records attributed to Daniel A Nicholson.

13 recordsLinked to original sources

PubMed2006

Distance-dependent differences in synapse number and AMPA receptor expression in hippocampal CA1 pyramidal neurons.

The ability of synapses throughout the dendritic tree to influence neuronal output is crucial for information processing in the brain. Synaptic potentials attenuate dramatically, however, as they propagate along dendrites toward the soma. To examine whether excitatory axospinous synapses on CA1 pyramidal neurons compensate for their distance from the soma to counteract such dendritic filtering, we evaluated axospinous synapse number and receptor expression in three progressively distal regions: proximal and distal stratum radiatum (SR), and stratum lacunosum-moleculare (SLM). We found that the proportion of perforated synapses increases as a function of distance from the soma and that their AMPAR, but not NMDAR, expression is highest in distal SR and lowest in SLM. Computational models of pyramidal neurons derived from these results suggest that they arise from the compartment-specific use of conductance scaling in SR and dendritic spikes in SLM to minimize the influence of distance on synaptic efficacy.

Animals↗

PubMed2004

Reduction in size of perforated postsynaptic densities in hippocampal axospinous synapses and age-related spatial learning impairments.

A central problem in the neurobiology of normal aging is why learning is preserved in some aged individuals yet impaired in others. To investigate this issue, we examined whether age-related deficits in spatial learning are associated with a reduction in postsynaptic density (PSD) area in hippocampal excitatory synapses (i.e., with a structural modification that is likely to have a deleterious effect on synaptic function). A hippocampus-dependent version of the Morris water maze task was used to separate Long-Evans male rats into young adult, aged learning-unimpaired, and equally aged learning-impaired groups. Axospinous synapses from the CA1 stratum radiatum were analyzed using systematic random sampling and serial section analyses. We report that aged learning-impaired rats exhibit a marked ( approximately 30%) and significant reduction in PSD area, whereas aged learning-unimpaired rats do not. The observed structural alteration involves a substantial proportion of perforated synapses but is not observed in nonperforated synapses. These findings support the notion that many hippocampal perforated synapses become less efficient in aged learning-impaired rats, which may contribute to cognitive decline during normal aging.

Aging↗

PubMed2004

Differences in the expression of AMPA and NMDA receptors between axospinous perforated and nonperforated synapses are related to the configuration and size of postsynaptic densities.

Axospinous synapses are traditionally divided according to postsynaptic density (PSD) configuration into a perforated subtype characterized by a complex-shaped PSD and nonperforated subtype exhibiting a simple-shaped, disc-like PSD. It has been hypothesized that perforated synapses are especially important for synaptic plasticity because they have a higher efficacy of impulse transmission. The aim of the present study was to test this hypothesis. The number of postsynaptic AMPA receptors (AMPARs) is widely regarded as the major determinant of synaptic efficacy. Therefore, the expression of AMPARs was evaluated in the two synaptic subtypes and compared with that of NMDA receptors (NMDARs). Postembedding immunogold electron microscopy was used to quantify the immunoreactivity following single labeling of AMPARs or NMDARs in serial sections through the CA1 stratum radiatum of adult rats. The results showed that all perforated synapses examined were immunopositive for AMPARs. In contrast, only a proportion of nonperforated synapses (64% on average) contained immunogold particles for AMPARs. The number of immunogold particles for AMPARs was markedly and significantly higher in perforated synapses than in immunopositive nonperforated synapses. Although all synapses of both subtypes were NMDAR immunopositive perforated synapses contained significantly more immunogold particles for NMDARs than nonperforated ones. Multivariate analysis of variance revealed that the mode of AMPAR and NMDAR expression is related to the complexity of PSD configuration, not only to PSD size. These findings support the notion that perforated synapses may evoke larger postsynaptic responses relative to nonperforated synapses and, hence, contribute to an enhancement of synaptic transmission associated with some forms of synaptic plasticity.

Animals↗

PubMed2004

Developmental changes in eyeblink conditioning and simple spike activity in the cerebellar cortex.

The activity of neurons in the cerebellum exhibits learning-related changes during eyeblink conditioning in adult mammals. The induction and preservation of learning-related changes in cerebellar neuronal activity in developing rats may be affected by the level of maturity in cerebellar feedback to its brainstem afferents, including the inferior olive. Developmental changes in cerebellar plasticity were examined by recording the activity of Purkinje cells in eye regions of cerebellar cortical lobule HVI (lobulus simplex) in infant rats during eyeblink conditioning. The percentage and amplitude of eyeblink conditioned responses increased as a function of age. Analyses of Purkinje cell simple spike activity revealed developmental increases in the number of units that exhibited stimulus-evoked and learning-related changes in activity. Moreover, the magnitude of these changes exhibited a substantial age-related increase. The results support the view that the emergence of learning-specific cerebellar plasticity and the ontogeny of eyeblink conditioning are influenced by developmental changes in the synaptic interactions within brainstem-cerebellum circuits.

Animals↗

PubMed2004

Selective developmental increase in the climbing fiber input to the cerebellar interpositus nucleus in rats.

Previous studies have demonstrated that learning-related cerebellar plasticity and stimulus-elicited neuronal activity emerge ontogenetically in parallel with delay eyeblink conditioning in rats. The present study examined cerebellar interpositus field potentials and multiunit neuronal activity evoked by microstimulation of the inferior olive in Postnatal Day 17 and 24 rats. The slope and amplitude of the excitatory postsynaptic potential and the number of evoked multiunit spikes increased with age, whereas the inhibitory postsynaptic potential caused by Purkinje cell input remained stable. These results are consistent with the notion that the postsynaptic depolarization of cerebellar interpositus neurons caused by cerebellar afferents (e.g., the climbing fibers of the inferior olive) is a critical factor contributing to the ontogeny of delay eyeblink conditioning in rats.

Animals↗

PubMed2004

Developmental changes in the neural mechanisms of eyeblink conditioning.

Eyeblink conditioning has been used as a model system for examining the ontogeny of associative learning and its neural basis in rodents. Associative eyeblink conditioning emerges between postnatal days (P) 17 and 24 in rats. Neurophysiological studies in infant rats during eyeblink conditioning revealed developmental changes in the activity of cerebellar neurons that correspond to the ontogenetic emergence of eyeblink conditioning. The developmental changes in cerebellar neuronal activity suggest that the ontogeny of eyeblink conditioning is related to changes in learning mechanisms rather than motor performance mechanisms. Additional neurophysiological and neuroanatomical studies demonstrated that the developmental changes in neuronal activity in the cerebellum are due to developmental changes in interactions between the cerebellum and its inputs, the inferior olive and pontine nuclei. Developmental changes in cerebellar inputs and regulation of its inputs affect the induction of learning-related plasticity, thereby affecting the rate and magnitude of conditioning.

Animals↗

PubMed2003

Developmental changes in evoked Purkinje cell complex spike responses.

The development of synaptic interconnections between the cerebellum and inferior olive, the sole source of climbing fibers, could contribute to the ontogeny of certain forms of motor learning (e.g., eyeblink conditioning). Purkinje cell complex spikes are produced exclusively by climbing fibers and exhibit short- and long-latency activity in response to somatosensory stimulation. Previous studies have demonstrated that evoked short- and long-latency complex spikes generally occur on separate trials and that this response segregation is regulated by inhibitory feedback to the inferior olive. The present experiment tested the hypothesis that complex spikes evoked by periorbital stimulation are regulated by inhibitory feedback from the cerebellum and that this feedback develops between postnatal days (PND) 17 and 24. Recordings from individual Purkinje cell complex spikes in urethan-anesthetized rats indicated that the segregation of short- and long-latency evoked complex spike activity emerges between PND17 and PND24. In addition, infusion of picrotoxin, a GABAA-receptor antagonist, into the inferior olive abolished the response pattern segregation in PND24 rats, producing evoked complex spike response patterns similar to those characteristic of younger rats. These data support the view that cerebellar feedback to the inferior olive, which is exclusively inhibitory, undergoes substantial changes in the same developmental time window in which certain forms of motor learning emerge.

Action Potentials↗

PubMed2003

Ontogeny of eyeblink conditioned response timing in rats.

Eyeblink conditioned response (CR) timing was assessed in adult and infant rats. In Experiment 1, adult rats were trained with a 150-ms tone conditioned stimulus (CS) paired with a periorbital shock unconditioned stimulus (US; presented at 200- or 500-ms interstimulus intervals [ISIs]). The rats acquired CRs with 2 distinct peaks that occurred just before the US onset times. Experiments 2 and 3 examined developmental changes in CR timing in pups trained on Postnatal Days 24-26 or 32-34. Experiment 3 used a delay conditioning procedure in which the tone CS continued throughout the ISIs. Pups of both ages exhibited robust conditioning. However, there were age-related increases in the percentage of double-peaked CRs and in CR timing precision. Ontogenetic changes in eyeblink CR timing may be related to developmental changes in cerebellar cortical or hippocampal function.

Aging↗

PubMed2003

Long-term retention of the classically conditioned eyeblink response in rats.

Retention of the classically conditioned eyeblink response in rats was tested with a conditioned stimulus (CS)-alone extinction test and 2 sessions of reacquisition training. Retention of the eyeblink conditioned response (CR) during both tests was highest 24 hr and 1 month after initial acquisition. Three months after initial acquisition, responding during the CS-alone test was at baseline, but there was significant savings during reacquisition. By 6 months after initial acquisition, the memory for the eyeblink CR was not expressed in either test. The group differences in retention, despite initial acquisition of the eyeblink CR to equal levels, suggest that rat eyeblink conditioning may provide a useful behavioral model for studying the neural processes underlying memory retention and loss.

Animals↗

PubMed2003

Addition of inhibition in the olivocerebellar system and the ontogeny of a motor memory.

The developmental emergence of learning has traditionally been attributed to the maturation of single brain regions necessary for learning in adults, rather than to the maturation of synaptic interactions within neural systems. Acquisition and retention of a simple form of motor learning, classical conditioning of the eyeblink reflex, depends on the cerebellum and interconnected brainstem structures, including the inferior olive. Here, we combined unit recordings from Purkinje cells in eye regions of the cerebellar cortex and quantitative electron microscopy of the inferior olive to show that the developmental emergence of eyeblink conditioning in rats is associated with the maturation of inhibitory feedback from the cerebellum to the inferior olive. The results are consistent with previous work in adult animals and indicate that the maturation of cerebellar inhibition within the inferior olive may be a critical factor for the formation and retention of learning-specific cerebellar plasticity and eyeblink conditioning.

Action Potentials↗

PubMed2002

Medial dorsal thalamic lesions impair blocking and latent inhibition of the conditioned eyeblink response in rats.

The effects of lesions of the medial dorsal thalamic nucleus (MD) on blocking and latent inhibition (LI) of the rat eyeblink response were examined in the present study. Previous work has demonstrated that the cingulate cortex and related thalamic areas are involved in processing conditioning stimuli throughout training. The experiments in the present study tested the hypothesis that disruption of cingulothalamic stimulus processing produced by lesions of the MD would impair 2 types of associative learning that involve decremental changes in attention. In Experiment 1, MD lesions severely impaired blocking. In Experiment 2, MD lesions severely impaired LI. The results indicate that lesions of the MD impair incremental, decremental, or both types of changes in stimulus processing during learning.

Animals↗

PubMed2002

Neuronal correlates of conditioned inhibition of the eyeblink response in the anterior interpositus nucleus.

Conditioned inhibition (CI) of the rat eyeblink response and the neuronal correlates of CI in the cerebellar interpositus nucleus were examined in the present study. In Experiment 1, CI was established with a novel, 3-group design. In Experiment 2, neuronal activity in the anterior interpositus nucleus was recorded during CI training and testing. Each rat was given 2 training phases and then tested for CI with summation and retardation tests. Rats given CI training showed behavioral inhibition compared with rats in 2 control groups. Neuronal activity in the anterior interpositus nucleus correlated with behavioral responding during discrimination training and during the summation test. The results suggest that neurons in the cerebellar anterior interpositus nucleus may participate in the acquisition or expression of CI.

Animals↗

PubMedDate not supplied

Blockade of GABAA receptors in the interpositus nucleus modulates expression of conditioned excitation but not conditioned inhibition of the eyeblink response.

The cerebellum and related brainstem structures are essential for excitatory eyeblink conditioning. Recent evidence indicates that the cerebellar interpositus and lateral pontine nuclei may also play critical roles in conditioned inhibition (CI) of the eyeblink response. The current study examined the role of GABAergic inhibition of the interpositus nucleus in retention of CI. Male Long-Evans rats were implanted with a cannula positioned just above or in the anterior interpositus nucleus before training. The rats were trained with two different tones and a light as conditioned stimuli, and a periorbital shock as the unconditioned stimulus. CI training consisted of four phases: 1) excitatory conditioning (8 kHz tone paired with shock); 2) feature-negative discrimination (2 kHz tone paired with shock or 2 kHz tone concurrent with light); 3) summation test (8 kHz tone or 8 kHz tone concurrent with light); and 4) retardation test (light paired with shock). After reaching a criterion level of performance on the feature-negative discrimination (40% discrimination), 0.5 microl picrotoxin (a GABAA receptor antagonist) was infused at one of four concentrations, each concentration infused during separate test sessions. Picrotoxin transiently impaired conditioned responses during trials with the excitatory stimulus (tone) in a dose-dependent manner, but did not significantly impact responding to the inhibitory compound stimulus (tone-light). The results suggest that expression of conditioned inhibition of the eyeblink conditioned response does not require GABAergic inhibition of neurons in the anterior interpositus nucleus.

Acoustic Stimulation↗