Guy Major

Persistent neural activity: prevalence and mechanisms.

Persistent neural activity refers to a sustained change in action potential discharge that long outlasts a stimulus. It is found in a diverse set of brain regions and organisms and several in vitro systems, suggesting that it can be considered a universal form of circuit dynamics that can be used as a mechanism for short-term storage and accumulation of sensory or motor information. Both single cell and network mechanisms are likely to co-operate in generating persistent activity in many brain areas.

Spatiotemporally graded NMDA spike/plateau potentials in basal dendrites of neocortical pyramidal neurons.

Glutamatergic inputs clustered over approximately 20-40 microm can elicit local N-methyl-D-aspartate (NMDA) spike/plateau potentials in terminal dendrites of cortical pyramidal neurons, inspiring the notion that a single terminal dendrite can function as a decision-making computational subunit. A typical terminal basal dendrite is approximately 100-200 microm long: could it function as multiple decision-making subunits? We test this by sequential focal stimulation of multiple sites along terminal basal dendrites of layer 5 pyramidal neurons in rat somatosensory cortical brain slices, using iontophoresis or uncaging of brief glutamate pulses. There was an approximately sevenfold spatial gradient in average spike/plateau amplitude measured at the soma, from approximately 3 mV for distal inputs to approximately 23 mV for proximal inputs. Spike/plateaus were NMDA receptor (NMDAR) conductance-dominated at all locations. Large Ca(2+) transients accompanied spike/plateaus over a approximately 10- to 40-microm zone around the input site; smaller Ca(2+) transients extended approximately uniformly to the dendritic tip. Spike/plateau duration grew with increasing glutamate and depolarization; high Ca(2+) zone size grew with spike/plateau duration. The minimum high Ca(2+) zone half-width (just above NMDA spike threshold) increased from distal (approximately 10 microm) to proximal locations (approximately 25 microm), as did the NMDA spike glutamate threshold. Depolarization reduced glutamate thresholds. Simulations exploring multi-site interactions based on this demonstrate that if appropriately timed and localized inputs occur in vivo, a single basal dendrite could correspond to a cascade of multiple co-operating dynamic decision-making subunits able to retain information for hundreds of milliseconds, with increasing influence on neural output from distal to proximal. Dendritic NMDA spike/plateaus are thus well-suited to support graded persistent firing.

NMDA and GABAB (KIR) Conductances: The “Perfect Couple” for Bistability

Networks that produce persistent firing in response to novel input patterns are thought to be important in working memory and other information storage functions. One possible mechanism for maintaining persistent firing is dendritic voltage bistability in which the depolarized state depends on the voltage dependence of the NMDA conductance at recurrent synapses. In previous models, the hyperpolarized state is dependent on voltage-independent conductances, including GABAA. The interplay of these conductances leads to bistability, but its robustness is limited by the fact that the conductance ratio must be within a narrow range. The GABAB component of inhibitory transmission was not considered in previous analyses. Here, we show that the voltage dependence of the inwardly rectifying potassium (KIR) conductance activated by GABAB receptors adds substantial robustness to network simulations of bistability and the persistent firing that it underlies. The hyperpolarized state is robust because, at hyperpolarized potentials, the GABAB/KIR conductance is high and the NMDA conductance is low; the depolarized state is robust because, at depolarized potentials, the NMDA conductance is high and the GABAB/KIR conductance is low. Our results suggest that this complementary voltage dependence of GABAB/KIR and NMDA conductances makes them a “perfect couple” for producing voltage bistability.

Integrating over time with dendritic wave-fronts

Temporal integration, in which transient inputs shift neurons between stable firing rates, is thought to require neural networks. A new modeling study now proposes that single neurons could perform this calculation via intracellular calcium release dynamics.