Turning on and off recurrent balanced cortical activity

Abstract

The vast majority of synaptic connections onto neurons in the cerebral cortex arise from other cortical neurons, both excitatory and inhibitory, forming local and distant 'recurrent' networks. Although this is a basic theme of cortical organization, its study has been limited largely to theoretical investigations, which predict that local recurrent networks show a proportionality or balance between recurrent excitation and inhibition, allowing the generation of stable periods of activity. This recurrent activity might underlie such diverse operations as short-term memory, the modulation of neuronal excitability with attention, and the generation of spontaneous activity during sleep. Here we show that local cortical circuits do indeed operate through a proportional balance of excitation and inhibition generated through local recurrent connections, and that the operation of such circuits can generate self-sustaining activity that can be turned on and off by synaptic inputs. These results confirm the long-hypothesized role of recurrent activity as a basic operation of the cerebral cortex.

Hallucinogen-Induced UP States in the Brain Slice of Rat Prefrontal Cortex: Role of Glutamate Spillover and NR2B-NMDA Receptors

“…For example, while late EPSCs received by the recorded neuron depend on stimulation of NR2B-containing NMDA receptors, these receptors may be widely distributed within the network. Consistent with previous work in this field (Sutor and Hablitz, 1989;Shu et al, 2003), manipulating NMDA receptor activation in the recorded neuron by changing the holding potential or with MK-801 open channel blockade (data not shown) does not prevent the occurrence of late EPSCs or UP states.…”

“…Electrophysiological studies in rats show that indolamine (eg lysergic acid diethylamine; LSD) and phenethlylamine (eg 1-(2,5-dimethoxy-4-iodophenyl-2-aminopropane (DOI)) hallucinogens enhance a delayed form of glutamate release through their partial agonist actions at 5-HT 2A receptors . This late wave of glutamate release depends on activation of NMDA receptors (Stutzmann et al, 2001) and resembles the UP states resulting from sustained activity in balanced excitatory and inhibitory recurrent networks described recently (Shu et al, 2003;Hasenstaub et al, 2005). In the adult rat prefrontal cortex, under typical submerged slice conditions, this phenomenon can be observed only infrequently in the absence of psychedelic hallucinogen (eg when a pathway is stimulated after a long quiescent period).…”

“…Glutamate spillover appears to be critical for triggering late EPSCs or UP states in submerged brain slice of the rat prefrontal cortex; however, it is known that such waves of activity depend on traditional synaptic transmission in a network of neurons (Sutor and Hablitz, 1989;Shu et al, 2003;Hasenstaub et al, 2005). This critical role of network activity complicates analysis of the mechanism underlying the enhancement of late EPSCs or UP states by psychedelic hallucinogens.…”

“…While the diffusion of glutamate appears highly regulated by glial and neuronal uptake mechanisms (reviewed in Huang and Bergles, 2004), dendritic spines in the cerebral cortex are unusual in their relative lack of glial cover (Spacek, 1985). Since spillover would preferentially activate high-affinity NMDA receptors, it has been suggested that under normal physiological conditions it would not interfere with fast point-to-point transmission but instead may enhance responsiveness of the network (Shu et al, 2003;Scimemi et al, 2004). In fact, there are aspects of the subjective effects of psychedelic hallucinogens that appear consistent with enhancing interactions between synapses that would normally not experience 'cross talk,'Fthat is, altered sensory perception, increased emotional lability, and disturbed cognitive processing.…”

Integrated Brain Circuits: Neuron-Astrocyte Interaction in Sleep-Related Rhythmogenesis

“…Interestingly, although the isolated cortical slices and cortical slabs can generate slow oscillations independently of the thalamus[30,47,50,51], there has been no formal quantitative analysis of the characteristics of cortical slow oscillations in the absence of the thalamus[52]. A recently proposed view of the slow oscillation suggests that this rhythm is generated by a synaptic-based cortical oscillator and two intrinsic thalamic oscillators: thalamocortical neurons and neurons of the TRN[52].…”