Biomedical subjects

John F Disterhoft

Publications and source records attributed to John F Disterhoft.

At least 19 recordsLinked to original sources

PubMed2026

Individual Differences in Cognitive Aging Rodent Datasets (ID-CARD): A collaborative platform for behavioral analysis across the lifespan.

Understanding cognitive aging requires approaches that capture individual variability while enabling integration across studies. In rodent models, behavioral data are central to this effort, yet cross-laboratory differences in experimental design limit comparability and constrain secondary analysis. To address this gap, we developed the Individual Differences in Cognitive Aging Rodent Datasets (ID-CARD), a first-of-its-kind collaborative repository aggregating trial-level Morris water maze data from multiple laboratories. ID-CARD is designed to support large-scale, integrative analyses and to facilitate secondary use of existing behavioral data in alignment with emerging data-sharing and transparency initiatives. Rather than imposing retrospective harmonization of experimental protocols, we implemented a normalization and modeling framework that enables comparison of learning trajectories while preserving meaningful variation across studies. Behavioral data from > 5000 rats spanning common strains, both sexes, and multiple ages were normalized in training and performance domains and fit with a logarithmic function to derive an error accumulation rate coefficient (EARC) as a measure of spatial learning. Age was strongly associated with increased EARC, indicating attenuated learning, even after adjusting for non-spatial cue performance. Analyses of goodness of fit revealed systematic structure in learning dynamics, where age was associated with reduced learning-curve conformity after accounting for overall performance. Inter-individual variability in spatial learning also increased with age, with strain-specific interactions. These findings demonstrate that integrated analysis of heterogeneous behavioral datasets can yield robust, individual-level insights into cognitive aging. ID-CARD provides a scalable resource and analytic framework to advance discovery in behavioral neuroscience by enabling reuse, integration, and comparative analysis of existing data.

Cognitive aging↗

PubMed2006

Learning, aging and intrinsic neuronal plasticity.

In vitro experiments indicate that intrinsic neuronal excitability, as evidenced by changes in the post-burst afterhyperpolarization (AHP) and spike-frequency accommodation, is altered during learning and normal aging in the brain. Here we review these studies, highlighting two consistent findings: (i) that AHP and accommodation are reduced in pyramidal neurons from animals that have learned a task; and (ii) that AHP and accommodation are enhanced in pyramidal neurons from aging subjects, a cellular change that might contribute to age-related learning impairments. Findings from in vivo single-neuron recording studies complement the in vitro data. From these consistently reproduced findings, we propose that the intrinsic AHP level might determine the degree of synaptic plasticity and learning. Furthermore, it seems that reductions in the AHP must occur before learning if young and aging subjects are to learn a task successfully.

Aging↗

PubMed2006

Vibrissa-signaled eyeblink conditioning induces somatosensory cortical plasticity.

Whisker deflection conditioned stimuli (CS) were demonstrated to activate physiologically and anatomically defined barrels in the contralateral somatosensory cortex and to support trace-eyeblink conditioned responses when paired with corneal airpuff unconditioned stimuli in rabbits. Analysis of cytochrome-oxidase-stained somatosensory whisker-associated cortical barrels revealed a row-specific expansion of the conditioned compared with the nontrained hemisphere. This expansion was not evident in pseudo-conditioned rabbits, suggesting that this expansion of conditioned cortical barrels in response to a hippocampal- and forebrain-dependent learning task (trace conditioning) is associative rather than activity dependent. Using whisker stimulation as a CS in the well studied eyeblink conditioning paradigm will facilitate characterizing sensory cortical involvement in controlling and modulating an associatively learned response at the neural systems and cellular level.

Animals↗

PubMed2006

Pharmacological and molecular enhancement of learning in aging and Alzheimer's disease.

When animals learn hippocampus-dependent associative and spatial tasks such as trace eyeblink conditioning and the water maze, CA1 hippocampal neurons become more excitable as a result of reductions in the post-burst, slow afterhyperpolarization. The calcium-activated potassium current that mediates this afterhyperpolarization is activated by the calcium influx that occurs when a series of action potentials fire and serves as a modulator of neuronal firing frequency. As a result, spike frequency accommodation is also reduced after learning. Neuronal calcium buffering processes change and/or voltage-dependent calcium currents increase during aging; leading to enhancements in the slow afterhyperpolarization, increased spike frequency accommodation and age-associated impairments in learning. We describe a series of studies done to characterize this learning-specific enhancement in intrinsic neuronal excitability and its converse in aging brain. We have also combined behavioral pharmacology and biophysics in experiments demonstrating that compounds that increase neuronal excitability in CA1 pyramidal neurons also enhance learning rate of hippocampus-dependent tasks, especially in aging animals. The studies reviewed here include those using nimodipine, an L-type calcium current blocker that tends to cross the blood-brain barrier; metrifonate, a cholinesterase inhibitor; CI1017, a muscarinic cholinergic agonist; and galantamine, a combined cholinesterase inhibitor and nicotinic agonist. Since aging is the chief risk factor for Alzheimer's disease, a disease that targets the hippocampus and associated brain regions and markedly impairs hippocampus-dependent learning, these compounds have potential use as treatments for this disease. Galantamine has been approved by the USDA for this purpose. Finally, we have extended our studies to the TG2576 transgenic mouse model of Alzheimer's disease (AD), that overproduces amyloid precursor protein (APP) and increases levels of toxic beta-amyloid in the brain. Not only do these mice show deficits in hippocampus-dependent learning as they age, but their hippocampal neurons show a reduced capacity to increase their levels of intrinsic excitability with reductions in the slow afterhyperpolarization after application of the muscarinic agonist carbachol. These TG2576 APP overproducing mice were crossed with BACE1 knockout mice, that do not produce beta-amyloid because cleavage of APP by the beta-site APP cleaving enzyme 1 (BACE1) is a critical step in its formation. Not only was hippocampus-dependent learning rescued in the bigenic TG2576-BACE1 mice, but the capacity of hippocampal neurons to show normal enhancements of intrinsic excitability was restored. The series of studies reviewed here support our hypothesis that enhancement in intrinsic excitability by reductions in calcium-activated potassium currents in hippocampal neurons is an important cellular mechanism for hippocampus-dependent learning.

Aging↗

PubMed2006

Temporal memory deficits in Alzheimer's mouse models: rescue by genetic deletion of BACE1.

Transgenic mouse models of Alzheimer's disease (AD) exhibit amyloid-beta (Abeta) accumulation and related cognitive impairments. Although deficits in hippocampus-dependent place learning have been well characterized in Alzheimer's transgenic mice, little is known about temporal memory function in these AD models. Here, we applied trace fear conditioning to two different Alzheimer's mouse models and investigated the relationship between pathogenic Abeta and temporal memory deficits. This behavioral test requires hippocampus-dependent temporal memory processing as the conditioned and unconditioned stimuli are separated by a trace interval of 30 s. We found that both amyloid precursor protein (APP) transgenic (Tg2576) and APP/presenilin (PS)1 transgenic (Tg6799) mice were impaired in memorizing this association across the time gap. Both transgenic groups performed as well as wild-type control mice in delay fear conditioning when the trace interval was removed, indicating that the trace conditioning deficits are hippocampus-specific. Importantly, Tg6799 mice engineered to lack the major Alzheimer's beta-secretase (beta-site APP-cleaving enzyme 1: BACE1) showed behavioral rescue from temporal memory deficits. Elevated levels of soluble Abeta oligomers found in Tg6799+ mouse brains returned to wild-type control levels without changes in APP/PS1 transgene expression in BACE1-/- * Tg6799+ bigenic mouse brains, suggesting Abeta oligomers as potential mediators of memory loss. Thus, trace fear conditioning is a useful assay to test the mechanisms and therapeutic interventions for Abeta-dependent deficits in temporal associative memory. Our gene-based approach suggests that lowering soluble Abeta oligomers by inhibiting BACE1 may be beneficial for alleviating cognitive disorders in AD.

Alzheimer Disease↗

PubMed2006

Differential effects of alphaCaMKII mutation on hippocampal learning and changes in intrinsic neuronal excitability.

Alpha-calcium/calmodulin-dependent kinase II (alphaCaMKII) is central to synaptic plasticity but it remains unclear whether this kinase contributes to neuronal excitability changes, which are a cellular correlate of learning. Using knock-in mice with a targeted T286A mutation that prevents the autophosphorylation of alphaCaMKII (alphaCaMKII(T286A)), we studied the role of alphaCaMKII signaling in regulating hippocampal neuronal excitability during hippocampus-dependent spatial learning in the Morris water maze. Wild-type control mice showed increased excitability of CA1 pyramidal neurons, as assessed by a reduction in the postburst afterhyperpolarization (AHP), after spatial training in the water maze. Importantly, wild-type mice did not show AHP changes when they were exposed to the water maze without the escape platform and swam the same amount of time as the trained mice (swim controls), thus manifesting learning-specific increases in hippocampal CA1 excitability associated with spatial training. Meanwhile, alphaCaMKII(T286A) mice showed impairments in spatial learning but exhibited reduced levels of AHP that were similar to wild-type controls after water-maze training. Notably, both trained and swim-control groups of alphaCaMKII(T286A) mutants showed similar increased excitability, indicating that swimming by itself is enough to induce changes in excitability in the absence of normal alphaCaMKII function. This result demonstrates dissociation of alphaCaMKII-independent changes in intrinsic neuron excitability from learning and synaptic plasticity mechanisms, suggesting that increases in excitability per se are not perfectly correlated with learning. Our findings suggest that alphaCaMKII signaling may function to suppress learning-unrelated changes during training, thereby allowing hippocampal CA1 neurons to increase their excitability appropriately for encoding spatial memories.

Action Potentials↗

PubMed2005

GLYX-13: a monoclonal antibody-derived peptide that acts as an N-methyl-D-aspartate receptor modulator.

We previously created a monoclonal antibody (MAb), B6B21, that acts as a partial agonist at the glycine site of the N-methyl-d-aspartate (NMDA) receptor [Moskal, J.R., Schaffner, A.E., 1986. Monoclonal antibodies to the dentate gyrus: immunocytochemical characterization and flow cytometric analysis of hippocampal neurons bearing a unique cell-surface antigen. J. Neurosci. 6, 2045-2053.]. The hypervariable region of the light chain of B6B21 was cloned and sequenced. Peptides were then synthesized based on this sequence information and screened using rat hippocampal membrane preparations to measure [(3)H]MK-801 binding in the presence of 7-chlorokynurenic acid, a glycine site-specific competitive inhibitor of NMDA receptor [Moskal, J.R., Yamamoto, H., Colley, P.A., 2001. The use of antibody engineering to create novel drugs that target N-methyl-d-aspartate receptors. Curr. Drug Targets 2, 331-345.]. Peptides that were able to increase [(3)H]MK-801 binding in a dose-dependent manner under these conditions were named Glyxins. Here we report that GLYX-13, a tetrapeptide (TPPT-amide), was found to readily cross the blood-brain barrier and modulate the NMDA receptor in a glycine-like fashion when examined pharmacologically and electrophysiologically. When GLYX-13 was administered to rats at 0.5-1.0mg/kg i.v., a significant enhancement in learning was observed using a hippocampus-dependent trace eye blink conditioning paradigm. These data indicate that the Glyxins are a new class of NMDA receptor modulators that may have therapeutic potential. Based on the broad agonist range in vitro and the potent cognitive-enhancing properties in a valid in vivo model of learning, GLYX-13 is a new drug candidate with potential for the treatment of cognitive disorders.

Animals↗

PubMed2005

Trace eyeblink conditioning requires the hippocampus but not autophosphorylation of alphaCaMKII in mice.

Little is known about signaling mechanisms underlying temporal associative learning. Here, we show that mice with a targeted point mutation that prevents autophosphorylation of alphaCaMKII (alphaCaMKII(T286A)) learn trace eyeblink conditioning normally. This forms a sharp contrast to the severely impaired spatial learning in the water maze and contextual fear conditioning observed in alphaCaMKII(T286A) mutants. Importantly, hippocampal lesions impaired trace eyeblink conditioning in alphaCaMKII(T286A) mice, suggesting a potential role of hippocampal alphaCaMKII-independent mechanisms. These results indicate that hippocampal signaling mechanisms that underlie temporal associative learning as assessed by trace eyeblink conditioning may differ from those of spatial and contextual learning.

Animals↗

PubMed2005

A fiber optic-based system for behavioral eyeblink measurement in a MRI environment.

We previously described a reliable system to control the timing of multiple stimuli and to detect behavioral eyeblink responses in fMRI studies of learning in animals. Here, we report a significant advancement of the original system, which incorporates a fiber-optic probe in order to avoid the interference associated with the application of pulsed field gradients during MR imaging, particularly echo planar imaging. Eyeblink responses recorded with our fiber-optic probe and modified detection circuit demonstrate the ability of our new system to acquire behavioral data free of gradient-induced artifacts, thereby eliminating the need for low-pass filtering. This fiber optic-based system should be applicable to both animal and human imaging experiments.

Animals↗

PubMed2005

Trace eyeblink conditioning in abstinent alcoholic individuals: effects of complex task demands and prior conditioning.

Chronic misuse of alcohol affects an integrated neural circuit supporting the formation of associative memories acquired during eyeblink classical conditioning (R. McGlinchey-Berroth et al., 1995). The authors of this study investigated single-cue trace conditioning in amnesic and nonamnesic abstinent alcoholic individuals who either were or were not trained in a single-cue delay conditioning task. Overall, untrained alcoholic participants were severely impaired in acquisition, and alcoholic participants previously trained in single-cue delay conditioning performed similarly to untrained control participants. Individual performance in acquisition varied significantly within task but was relatively stable between the trace and delay tasks; there were nonamnesic and amnesic alcoholic participants who acquired responses at a normal rate in both delay and trace conditioning. The similarity of performances in delay and trace conditioning suggests a common source of impairment across both tasks.

Acoustic Stimulation↗

PubMed2004

Slow afterhyperpolarization governs the development of NMDA receptor-dependent afterdepolarization in CA1 pyramidal neurons during synaptic stimulation.

CA1 pyramidal neurons from animals that have acquired a hippocampus-dependent task show a reduced slow postburst afterhyperpolarization (sAHP). To understand the functional significance of this change, we examined and characterized the sAHP activated by different patterns of synaptic stimuli and its impact on postsynaptic signal integration. Whole cell current-clamp recordings were performed on rat CA1 pyramidal neurons, and trains of stratum radiatum stimuli varying in duration, frequency, and intensity were used to activate the AHP. At -68 mV, a short train of subthreshold stimuli (20-150 Hz) generated only the medium AHP. In contrast, just two suprathreshold stimuli >50 Hz triggered a prominent sAHP sensitive to bath-applications of isoproterenol, carbachol, or intracellularly applied BAPTA, suggesting that the underlying current is the Ca2+-activated K+ current, the sIAHP. The sAHP magnitude was positively related to stimulus train duration and frequency, consistent with its dependence on intracellular Ca2+ accumulation for activation. About 20% of neurons recorded did not have a sAHP. In response to high-frequency suprathreshold stimuli, these neurons developed a pronounced afterdepolarization (ADP) and multiple action potential firing. The ADP magnitude increased with successive stimuli and was positively related to stimulus intensity and frequency. It was sensitive to bath-applications of thapsigargin and nitrendipine, and abolished by d-AP5, indicating that it is supported by intracellular Ca2+ release, the L-type Ca2+ influx, and N-methyl-D-aspartate (NMDA) receptor-mediated influx. In the presence of D-AP5, we were unable to trigger an ADP with maximal stimulus intensity. Pharmacologically eliminating the sAHP allowed neurons to develop an ADP with the original stimulus train. We propose that the slow AHP acts to facilitate Mg2+ re-block of the activated NMDA receptors, thereby reducing temporal summation and preventing an NMDA receptor-dependent ADP during intense synaptic events. Neuromodulation of the sAHP may thus affect information throughput and regulate NMDA receptor-mediated plasticity.

2-Amino-5-phosphonovalerate↗

PubMed2004

BACE1 deficiency rescues memory deficits and cholinergic dysfunction in a mouse model of Alzheimer's disease.

beta-site APP cleaving enzyme 1 (BACE1) is the beta-secretase enzyme required for generating pathogenic beta-amyloid (Abeta) peptides in Alzheimer's disease (AD). BACE1 knockout mice lack Abeta and are phenotypically normal, suggesting that therapeutic inhibition of BACE1 may be free of mechanism-based side effects. However, direct evidence that BACE1 inhibition would improve cognition is lacking. Here we show that BACE1 null mice engineered to overexpress human APP (BACE1(-/-).Tg2576(+)) are rescued from Abeta-dependent hippocampal memory deficits. Moreover, impaired hippocampal cholinergic regulation of neuronal excitability found in the Tg2576 AD model is ameliorated in BACE1(-/-).Tg2576(+) bigenic mice. The behavioral and electrophysiological rescue of deficits in BACE1(-/-).Tg2576(+) mice is correlated with a dramatic reduction of cerebral Abeta40 and Abeta42 levels and occurs before amyloid deposition in Tg2576 mice. Our gene-based approach demonstrates that lower Abeta levels are beneficial for AD-associated memory impairments, validating BACE1 as a therapeutic target for AD.

Alzheimer Disease↗

PubMed2004

Biophysical alterations of hippocampal pyramidal neurons in learning, ageing and Alzheimer's disease.

A series of behavioral, electrophysiological, and molecular biochemical experiments are reviewed indicating that when animals learn hippocampus-dependent tasks, output neurons in the CA1 and CA3 hippocampal subfields show reductions in the slow, post-burst afterhyperpolarization (AHP). The slow AHP is mediated by an apamin-insensitive calcium-activated potassium current. A reduction in the slow AHP makes hippocampal neurons more excitable and facilitates NMDA receptor-mediated response and temporal summation. During normal aging and in a mouse model of Alzheimer's disease (AD), the slow AHP is increased, making neurons less excitable and making learning more difficult. The subgroup of aging animals that are able to learn demonstrates the capacity to increase neuronal excitability by reducing the size of the slow AHP. Similarly, in a mouse model of AD, mice that are able to learn normally after a genetic alteration have a normal capacity for increasing hippocampal neuron excitability by reducing their slow AHP. We suggest that reduction in the slow AHP is basic to learning in young and aging animals. Inability to modulate the slow AHP contributes to learning deficits that occur during aging and early stages of AD.

Aging↗

PubMed2003

fMRI of the conscious rabbit during unilateral classical eyeblink conditioning reveals bilateral cerebellar activation.

The relative contributions of the ipsilateral and contralateral cerebellar cortex and deep nuclei to delay eyeblink conditioning have been debated and are difficult to survey entirely using typical electrophysiological and lesion techniques. To address these issues, we used single-event functional magnetic resonance imaging (fMRI) in the conscious rabbit to visualize the entire cerebellum simultaneously during eyeblink conditioning sessions. Examination of the blood oxygenation level-dependent (BOLD) response to a visual conditioning stimulus early in training revealed significant bilateral learning-related increases in the BOLD response in the anterior interpositus nucleus (IPA) and significant bilateral deactivation in hemispheric lobule VI (HVI) of the cerebellar cortex. Later in training, the BOLD response remained bilateral in the cortex and predominantly ipsilateral in the IPA. Conditioning stimulus-alone trials after conditioning revealed that both sides of HVI were affected similarly but that only the ipsilateral interpositus nucleus was activated. These results suggest that both sides of HVI normally influence the side of the IPA being conditioned and illustrate how fMRI can be used to examine multiple brain regions simultaneously in an awake, behaving animal to discover more rapidly the neural substrates of learning and memory.

Animals↗

PubMed2003

Functional magnetic resonance imaging in the awake rabbit: a system for stimulus presentation and response detection during eyeblink conditioning.

We describe a reliable system to control the timing of multiple stimuli and to detect eyeblink responses during functional magnetic resonance imaging (fMRI). The methods for stimulus delivery and timing, eyeblink detection, and response quantification are described in detail. We are using these methods in awake rabbits to study eyeblink conditioning (EBC) as a model paradigm for the study of learning and memory. Examples of conditioned eyeblinks in the awake rabbit during fMRI are presented for validation of our techniques. The results indicate that eyeblinks can be reliably recorded during fMRI, and that neither the stimulus delivery nor the response detection interferes with each other or affect the quality of the images. The combined fMRI/behavioral techniques should be useful for examining the entire brain simultaneously during the associative learning of a conditioned reflex in an animal model system.

Animals↗

PubMed2003

Lubeluzole and conditioned learning after cerebral ischemia.

Lubeluzole [S-4-(2-benzothiazolylmethylamino)-alpha-((3,4-difluorophenoxy)methyl)-1-piperidineethanol] reduces the severity of cerebral injury in animal models of brain ischemia. Its beneficial effects may include decreased concentration of extracellular glutamate, blockade of sodium and calcium channels, and attenuation of nitric oxide-mediated neuronal death. Previous studies have shown that global cerebral ischemia in rabbits impaired the subsequent acquisition of a trace-conditioned eyeblink reflex. Here, we examined the effect of preischemic treatment with lubeluzole on the acquisition of a trace-conditioned eyeblink response after 6.5 min of global cerebral ischemia. Three groups of rabbits underwent cerebral ischemia: one group underwent ischemia alone (I) and two groups underwent ischemia and also received lubeluzole (L(1), 1.25 mg/kg, and L(2), 2.5 mg/kg). All animals were subsequently trained using classical trace conditioning. Each training session consisted of the presentation of the conditioned stimulus (an 85-dB, 6-kHz auditory tone lasting for 100 ms) followed by a trace interval (a period of 300 ms during which no external stimulus was delivered) followed finally by the delivery of the unconditioned stimulus (a 150-ms puff of air directed at the cornea). We found that animals receiving preischemic administration of 1.25 mg/kg of lubeluzole demonstrated a significantly improved acquisition of the trace-conditioned reflex as compared to animals that did not receive lubeluzole. This finding demonstrates improved long-term neurobehavioral outcome with preischemic administration of 1.25 mg/kg of lubeluzole.

Animals↗

PubMed2003

Watermaze learning enhances excitability of CA1 pyramidal neurons.

The dorsal hippocampus is crucial for learning the hidden-platform location in the hippocampus-dependent, spatial watermaze task. We have previously demonstrated that the postburst afterhyperpolarization (AHP) of hippocampal pyramidal neurons is reduced after acquisition of the hippocampus-dependent, temporal trace eyeblink conditioning task. We report here that the AHP and one or more of its associated currents (IAHP and/or sIAHP) are reduced in dorsal hippocampal CA1 pyramidal neurons from rats that learned the watermaze task as compared with neurons from control rats. This reduction was a learning-induced phenomenon as the AHP of CA1 neurons from rats that failed to learn the hidden-platform location was similar to that of neurons from control rats. We propose that reduction of the AHP in pyramidal neurons in regions crucial for learning is a cellular mechanism of learning that is conserved across species and tasks.

Action Potentials↗

PubMed2003

Activity profiles of single neurons in caudal anterior cingulate cortex during trace eyeblink conditioning in the rabbit.

Acquisition of trace eyeblink conditioning involves the association of a conditioned stimulus (CS) with an unconditioned stimulus (US) separated by a stimulus-free trace interval. This form of conditioning is dependent upon the hippocampus and the caudal anterior cingulate cortex (AC), in addition to brain stem and cerebellar circuitry. Hippocampal involvement in trace eyeblink conditioning has been studied extensively, but the involvement of caudal AC is less well understood. In the present study, we compared neuronal responses from rabbits given either paired (trace conditioning) or unpaired (pseudoconditioning) presentations of the CS and US. Presentation of the CS elicited significant increases in neuronal activity at the onset of both trace conditioning and pseudoconditioning. A robust CS-elicited neuronal response persisted throughout the first 2 days of trace conditioning, declining gradually across subsequent training sessions. In contrast, the magnitude of the CS-elicited excitatory response during pseudoconditioning began to decline within the first 10 trials. Neurons exhibiting excitatory responses to the CS during trace conditioning also exhibited excitatory responses to the US that were significantly greater in magnitude than US-elicited responses during pseudoconditioning. CS-elicited decreases in neuronal activity became more robust over the course of trace conditioning compared to pseudoconditioning. Reductions in activity during the CS interval consistently preceded excitation in both training groups, suggesting that the CS-elicited decreases in neuronal activity may serve to increase the signal-to-noise ratio of the excitatory response to the tone. Taken together, these data suggest that the caudal AC is involved early in trace eyeblink conditioning and that maintenance of the CS-elicited excitatory response may serve to signal the salience of the tone.

Animals↗