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Kim T Blackwell

Publications and source records attributed to Kim T Blackwell.

10 recordsLinked to original sources
PubMed2006

Transient calcium and dopamine increase PKA activity and DARPP-32 phosphorylation.

Reinforcement learning theorizes that strengthening of synaptic connections in medium spiny neurons of the striatum occurs when glutamatergic input (from cortex) and dopaminergic input (from substantia nigra) are received simultaneously. Subsequent to learning, medium spiny neurons with strengthened synapses are more likely to fire in response to cortical input alone. This synaptic plasticity is produced by phosphorylation of AMPA receptors, caused by phosphorylation of various signalling molecules. A key signalling molecule is the phosphoprotein DARPP-32, highly expressed in striatal medium spiny neurons. DARPP-32 is regulated by several neurotransmitters through a complex network of intracellular signalling pathways involving cAMP (increased through dopamine stimulation) and calcium (increased through glutamate stimulation). Since DARPP-32 controls several kinases and phosphatases involved in striatal synaptic plasticity, understanding the interactions between cAMP and calcium, in particular the effect of transient stimuli on DARPP-32 phosphorylation, has major implications for understanding reinforcement learning. We developed a computer model of the biochemical reaction pathways involved in the phosphorylation of DARPP-32 on Thr34 and Thr75. Ordinary differential equations describing the biochemical reactions were implemented in a single compartment model using the software XPPAUT. Reaction rate constants were obtained from the biochemical literature. The first set of simulations using sustained elevations of dopamine and calcium produced phosphorylation levels of DARPP-32 similar to that measured experimentally, thereby validating the model. The second set of simulations, using the validated model, showed that transient dopamine elevations increased the phosphorylation of Thr34 as expected, but transient calcium elevations also increased the phosphorylation of Thr34, contrary to what is believed. When transient calcium and dopamine stimuli were paired, PKA activation and Thr34 phosphorylation increased compared with dopamine alone. This result, which is robust to variation in model parameters, supports reinforcement learning theories in which activity-dependent long-term synaptic plasticity requires paired glutamate and dopamine inputs.

Calcium↗
PubMed2006

An efficient stochastic diffusion algorithm for modeling second messengers in dendrites and spines.

Intracellular signaling pathways, which encompass both biochemical reactions and second messenger diffusion, interact non-linearly with neuronal membrane properties in their role as essential intermediaries for synaptic plasticity and neuromodulation. Computational modeling is a productive approach for investigating these phenomena; however, most current strategies for modeling neurons exclude signaling pathways. To overcome this deficiency, a new algorithm is presented to simulate stochastic diffusion in a highly efficient manner. The gain in speed is obtained by considering collections of molecules, instead of tracking the movement of individual molecules. The probability of a molecule leaving a spatially discrete compartment is used to create a lookup table that stores the probability of k(m) molecules leaving the compartment as a function of the total number of molecules in the compartment. During the simulation, the number of molecules leaving the compartment is determined using a uniform random number as an index into the lookup table. Simulations illustrate the accuracy of this algorithm by comparing it with the theoretical solution for deterministic diffusion. Additional simulations show how spines on a dendritic branch compartmentalize diffusible molecules. The efficiency of the algorithm is sufficient to allow simulation of second messenger pathways in a multitude of spines on an entire neuron.

Algorithms↗
PubMed2006

Subcellular, cellular, and circuit mechanisms underlying classical conditioning in Hermissenda crassicornis.

A breakthrough for studying the neuronal basis of learning emerged when invertebrates with simple nervous systems, such as the sea slug Hermissenda crassicornis, were shown to exhibit classical conditioning. Hermissenda learns to associate light with turbulence: prior to learning, naive animals move toward light (phototaxis) and contract their foot in response to turbulence; after learning, conditioned animals delay phototaxis in response to light. The photoreceptors of the eye, which receive monosynaptic inputs from statocyst hair cells, are both sensory neurons and the first site of sensory convergence. The memory of light associated with turbulence is stored as changes in intrinsic and synaptic currents in these photoreceptors. The subcellular mechanisms producing these changes include activation of protein kinase C and MAP kinase, which act as coincidence detectors because they are activated by convergent signaling pathways. Pathways of interneurons and motorneurons, where additional changes in excitability and synaptic connections are found, contribute to delayed phototaxis. Bursting activity recorded at several points suggest the existence of small networks that produce complex spatiotemporal firing patterns. Thus, the change in behavior may be produced by a nonlinear transformation of spatiotemporal firing patterns caused by plasticity of synaptic and intrinsic channels. The change in currents and the activation of PKC and MAPK produced by associative learning are similar to those observed in hippocampal and cerebellar neurons after rabbit classical conditioning, suggesting that these represent general mechanisms of memory storage. Thus, the knowledge gained from further study of Hermissenda will continue to illuminate mechanisms of mammalian learning.

Animals↗
PubMed2005

A comparative voltage and current-clamp analysis of feedback and feedforward synaptic transmission in the striatal microcircuit in vitro.

Striatal spiny projection (SP) neurons control movement initiation by integrating cortical inputs and inhibiting basal ganglia outputs. Central to this control lies a "microcircuit" that consists of a feedback pathway formed by axon collaterals between GABAergic SP neurons and a feedforward pathway from fast spiking (FS) GABAergic interneurons to SP neurons. Here, somatically evoked postsynaptic potentials (PSPs) and currents (PSCs) were compared for both pathways with dual whole cell patch recording in voltage- and current-clamp mode using cortex-striatum-substantia nigra organotypic cultures. On average, feedforward inputs were 1 ms earlier, more reliable, and about twice as large in amplitude compared with most feedback inputs. On the other hand, both pathways exhibited widely varying, partially overlapping amplitude distributions. This variability was already established for single FS neurons targeting many SP neurons. In response to precisely timed action potential bursts, feedforward and feedback inputs consistently showed short-term depression < or =50-70% in voltage-clamp, although feedback inputs also displayed strong augmentation in current-clamp in line with previous reports. The augmentation of feedback inputs was absent in gramicidin D perforated-patch recording, which also showed the natural reversal potential for both inputs to be near firing threshold. Preceding depolarizing feedback inputs during the down state did not consistently change subsequent postsynaptic action potentials. We conclude that feedback and feedforward inputs have their dominant effect during the up-state. The reversal potential close to the up-state potential, which supports shunting operation with millisecond precision and the strong synaptic depression, should enable both pathways to carry time-critical information.

Action Potentials↗
PubMed2003

Quantitative estimate of synaptic inputs to striatal neurons during up and down states in vitro.

Up states are prolonged membrane potential depolarizations critical for synaptic integration and action potential generation in cortical and striatal neurons. They commonly result from numerous concurrent synaptic inputs, whereas neurons reside in a down state when synaptic inputs are few. By quantifying the composition, frequency, and amplitude of synaptic inputs for both states, we provide important constraints for state transitions in striatal network dynamics. Up and down states occur naturally in cortex-striatum-substantia nigra cocultures, which were used as an in vitro model in the present study. Spontaneous synaptic inputs during down states were extracted automatically in spiny projection neurons and fast spiking interneurons of the striatum using a newly developed computer algorithm. Consistent with a heterogeneous population of synaptic inputs, PSPs and PSCs showed no correlation in amplitude and rise time and occurred at relatively low frequencies of 10-40 Hz during the down state. The number of synaptic inputs during up states, estimated from the up-state charge and the unitary charge of down-state PSCs, was 217 +/- 44. Given the average up-state duration of 284 +/- 34 msec, synaptic input frequency was approximately 800 Hz during up-states for both neuronal types. Many down-state events reversed at the chloride reversal potential and were blocked by GABA(A) antagonists. The high correlation between up- and down-state reversal potential suggests that despite these drastic changes in synaptic input frequency, the ratio of inhibitory to excitatory currents is similar during both states.

Action Potentials↗
PubMed2003

Comparison of Hermissenda type a and type B photoreceptors: response to light as a function of intensity and duration.

Hermissenda crassicornis is an invertebrate model used to study classical conditioning using light as the conditioned stimulus. The memory of the association is stored in type B photoreceptors, the output of which depends on interactions with type A photoreceptors. To understand the effect of classical conditioning on the output of type B photoreceptors in response to light, we measured the effect of light duration and intensity on membrane potential in both photoreceptor types of Hermissenda. The results show that, independent of light stimulus, the afterhyperpolarization is significantly greater in type A than in type B photoreceptors. In response to light, the generator potential (GP) rises linearly with an increase in either intensity or duration for both type A and type B photoreceptors. However, the difference between type A and type B photoreceptors depends on the time after light onset; the increase in peak GP with intensity is steeper in type A than type B, but by 14 sec after light onset, membrane potential is greater in type B than type A photoreceptors. Similarly, firing frequency increases with intensity and duration in both photoreceptor types but with a difference that is time dependent. During the first second after light onset, type A photoreceptors have a significantly higher firing frequency than type B photoreceptors; after this time, firing frequency is higher in type B than type A photoreceptors. Although membrane potential is correlated with firing frequency, this correlation is much lower in type A than type B photoreceptors, suggesting that some other conductance influences firing frequency in type A photoreceptors.

Action Potentials↗
PubMed2002

The effect of intensity and duration on the light-induced sodium and potassium currents in the Hermissenda type B photoreceptor.

Light duration and intensity influence classical conditioning in Hermissenda through their effects on the light-induced currents. Furthermore, the contribution of voltage-dependent potassium currents to the long-lasting depolarization in type B photoreceptors depends on light-induced currents active at resting potentials. Thus, the present study measures the effect of holding potential, duration, and intensity on the light-induced currents in discontinuous single-electrode voltage clamp mode. Three distinct current components are distinguished by their temporal and voltage characteristics and sensitivity to pharmacological agents. One current component is a transient sodium current, I(Nalgt); another is a plateau sodium current, I(plateau), which persists for the duration of the light stimulus. Substitution of trimethylammonium chloride for sodium reduces both currents equally, suggesting that I(plateau) represents partial inactivation of I(Nalgt). The third current component is a prolonged reduction in potassium currents, I(Klgt); it is accompanied by an increase in input resistance, and it appears at potentials close to rest. An increase in light duration or intensity causes an increase in the peak conductance of both I(Nalgt) and I(Klgt). Latency of I(Nalgt) is decreased by intensity, whereas rise time is increased by duration. An increase in light duration or intensity causes an increase in the time-to-peak and duration of I(Klgt). Characteristics of these currents suggest that I(Klgt) is responsible for the long-lasting depolarization seen after light termination, and thus plays a role in classical conditioning.

Action Potentials↗
PubMedDate not supplied

Subcellular interactions between parallel fibre and climbing fibre signals in Purkinje cells predict sensitivity of classical conditioning to interstimulus interval.

Classical conditioning of the nictitating membrane response requires a specific temporal interval between conditioned stimulus and unconditioned stimulus, and produces an increase in Protein Kinase C (PKC) activation in Purkinje cells. To evaluate whether biochemical interactions within the Purkinje cell may explain the temporal sensitivity, a model of PKC activation by Ca2+, diacylglycerol (DAG), and arachidonic acid (AA) is developed. Ca2+ elevation is due to CF stimulation and IP3 induced Ca2+ release (IICR). DAG and IP3 result from PF stimulation, while AA results from phospholipase A2 (PLA2). Simulations predict increased PKC activation when PF stimulation precedes CF stimulation by 0.1 to 3 s. The sensitivity of IICR to the temporal relation between PF and CF stimulation, together with the buffering system of Purkinje cells, significantly contribute to the temporal sensitivity.

Algorithms↗
PubMedDate not supplied

Paired turbulence and light do not produce a supralinear calcium increase in Hermissenda.

The sea slug Hermissenda learns to associate light and hair cell stimulation, but not when the stimuli are temporally uncorrelated. Memory storage, which requires an elevation in calcium, occurs in the photoreceptors, which receive monosynaptic input from hair cells that sense acceleration stimuli such as turbulence. Both light and hair cell activity increase calcium concentration in the photoreceptor, but it is unknown whether paired calcium signals combine supralinearly to initiate memory storage. A correlate of memory storage is an enhancement of the long lasting depolarization (LLD) after light offset, which is attributed to a reduction in voltage dependent potassium currents; however, it is unclear what causes the LLD in the untrained animal. These issues were addressed using a multi-compartmental computer model of phototransduction, calcium dynamics, and ionic currents of the Hermissenda photoreceptor. Simulations of the interaction between light and hair cell activity show that paired stimuli do not produce a greater calcium increase than unpaired stimuli. This suggests that hair cell activity is acting via some other pathway to initiate memory storage. In addition, simulations show that a potassium leak channel, which closes with an increase in calcium, is required to produce both the untrained LLD and the enhanced LLD due to the decrease in voltage dependent potassium currents. Thus, the expression of this correlate of classical conditioning may depend on a leak potassium current.

Animals↗