Jason N. MacLean

Internal Dynamics Determine the Cortical Response to Thalamic Stimulation

Although spontaneous activity occurs throughout the neocortex, its relation to the activity produced by external or sensory inputs remains unclear. To address this, we used calcium imaging of mouse thalamocortical slices to reconstruct, with single-cell resolution, the spatiotemporal dynamics of activity of layer 4 in the presence or absence of thalamic stimulation. We found spontaneous neuronal coactivations corresponded to intracellular UP states. Thalamic stimulation of sufficient frequency (>10 Hz) triggered cortical activity, and UP states, indistinguishable from those arising spontaneously. Moreover, neurons were activated in identical and precise spatiotemporal patterns in thalamically triggered and spontaneous events. The similarities between cortical activations indicate that intracortical connectivity plays the dominant role in the cortical response to thalamic inputs. Our data demonstrate that precise spatiotemporal activity patterns can be triggered by thalamic inputs and indicate that the thalamus serves to release intrinsic cortical dynamics.

Activity-Independent Homeostasis in Rhythmically Active Neurons

The shal gene encodes the transient potassium current (I(A)) in neurons of the lobster stomatogastric ganglion. Overexpression of Shal by RNA injection into neurons produces a large increase in I(A), but surprisingly little change in the neurons firing properties. Accompanying the increase in I(A) is a dramatic and linearly correlated increase in the hyperpolarization-activated inward current (I(h)). The enhanced I(h) electrophysiologically compensates for the enhanced I(A), since pharmacological blockade of I(h) uncovers the physiological effects of the increased I(A). Expression of a nonfunctional mutant Shal also induces a large increase in I(h), demonstrating a novel activity-independent coupling between the Shal protein and I(h) enhancement. Since I(A) and I(h) influence neuronal activity in opposite directions, our results suggest a selective coregulation of these channels as a mechanism for constraining cell activity within appropriate physiological parameters.

NMDA Receptor-mediated Oscillatory Properties: Potential Role in Rhythm Generation in the Mammalian Spinal Cord

Abstract: Previous studies have demonstrated that (1) NMDA receptor activation occurs during locomotor network operation in lower and higher vertebrates and (2) NMDA induces active membrane properties that can be expressed as intrinsic voltage fluctuations in cells located in the spinal cord of lower vertebrates, as well as in neurons located in supraspinal regions of the mammalian nervous system. This paper reviews recent data showing that NMDA can induce similiar inherent membrane potential behavior in synaptically isolated motoneurons and interneurons in the mammalian (in vitro neonatal rat) spinal cord. These TTX‐resistant voltage fluctuations include rhythmic oscillations and plateau potentials, as well as low‐frequency long‐lasting voltage shifts (LLVSs). 5‐HT facilitates the transformation of LLVSs into oscillatory events, and 5‐HT receptor antagonists have the reverse effect. In the absence of TTX, locomotor‐related rhythmic drive potentials in spinal cord neurons can display nonlinear voltage behavior compatible with NMDA receptor activation, although other voltage‐activated conductances are not excluded. Suppression of the nonlinear voltage response associated with NMDA receptor activation, via removal of Mg2+, disrupts locomotor patterns of network activity. The potential role of NMDA receptor activation in the operation of mammalian locomotor networks is discussed in the context of these recent observations.

NMDA Receptor Activation Triggers Voltage Oscillations, Plateau Potentials and Burstinq in Neonatal Rat Lumbar Motoneurons ln Vitro

Whole‐cell recordings of lumbar motoneurons in the intact neonatal rat spinal cord in vitro were undertaken to examine the effects of Kmethyl‐D‐aspartate (NMDA) receptor activation on membrane behaviour. Bath application of NMDA induced rhythmic voltage oscillations of 5.9 ± 2.1 mV (SD) at a frequency of 4.4 ± 1.5 Hz. Amplitude, but not frequency, of the voltage oscillations was membrane potential‐dependent. Voltage oscillations could recruit action potentials and/or plateau potentials with or without superimposed bursting. Blockade of synaptic transmission with tetrodotoxin (TTX) sometimes resulted in a loss of oscillatory activity which could then be restored by increasing the NMDA concentration. After application of TTX, the trajectory of NMDA‐induced oscillations was similar to the trajectory induced in the presence of intact synaptic networks, although the mean oscillation duration was longer and the oscillation frequency was slower (1.8 ± 1.1 Hz). Current ramps delivered after bath application of NMDA demonstrated bistable membrane properties which may underlie the plateau potentials. Injection of intracellular current pulses could initiate, entrain and terminate individual plateau potentials. The results suggest that membrane depolarization produced by oscillations may activate other intrinsic conductances which generate plateau potentials, thereby providing the neuron with enhanced voltage sensitivity, compared to that produced by NMDA receptor activation alone. These oscillatory events may have a role in the regulation of motor output in a variety of rhythmic behaviours including locomotion.

A visual thalamocortical slice

We describe a thalamocortical slice preparation in which connectivity between the mouse lateral geniculate nucleus (LGN) and primary visual cortex (V1) is preserved. Through DiI injections in fixed brains we traced and created a three-dimensional model of the mouse visual pathways. From this computer model we designed a slice preparation that contains a projection from LGN to V1. We prepared brain slices with these predicted coordinates and demonstrated anatomical LGN-V1 connectivity in these slices after LGN tracer injections. We also revealed functional LGN-V1 connectivity by stimulating LGN electrically and detecting responses in layer 4 of V1 using calcium imaging, field potential recordings and whole-cell recordings. We also identified layer-4 neurons that receive direct thalamocortical input. Finally, we compared cortical activity after LGN stimulation with spontaneous cortical activity and found significant overlap of the spatiotemporal dynamics generated by both types of events.

Lamina VII neurons are rhythmically active during locomotor-like activity in the neonatal rat spinal cord

The midsagittally-sectioned lumbar spinal cord with thoracic segments intact retains the capacity for locomotor-like activity. Intracellular recordings were used to characterize the activity and concurrently label lumbar neurons in lamina VII, an area previously implicated in the generation of locomotion. Sharp electrodes were shown to preferentially impale larger neurons. These neurons undergo rhythmic voltage oscillations, presumably synaptically driven, during locomotor-like activity induced by bath application of N-methyl-D-aspartate and 5-hydroxytryptamine. This supports the hypothesis that synaptic activity recruits neurons in lamina VII that are associated with locomotor behavior.

UP States Protect Ongoing Cortical Activity from Thalamic Inputs

Cortical neurons in vitro and in vivo fluctuate spontaneously between two stable membrane potentials: a depolarized UP state and a hyperpolarized DOWN state. UP states temporally correspond with multineuronal firing sequences which may be important for information processing. To examine how thalamic inputs interact with ongoing cortical UP state activity, we used calcium imaging and targeted whole-cell recordings of activated neurons in thalamocortical slices of mouse somatosensory cortex. Whereas thalamic stimulation during DOWN states generated multineuronal, synchronized UP states, identical stimulation during UP states had no effect on the subthreshold membrane dynamics of the vast majority of cells or on ongoing multineuronal temporal patterns. Both thalamocortical and corticocortical PSPs were significantly reduced and neuronal input resistance was significantly decreased during cortical UP states – mechanistically consistent with UP state insensitivity. Our results demonstrate that cortical dynamics during UP states are insensitive to thalamic inputs.

The upshot of up states in the neocortex: from slow oscillations to memory formation.

A sleeping brain is by no means dormant: most cortical neurons, primarily detached from the influence of stimuli in the environment, are nevertheless active, just as they are during behavior. Although neural activity is preserved during sleep, the structure of the activity changes significantly,

Default activity patterns at the neocortical microcircuit level.

Even in absence of sensory stimuli cortical networks exhibit complex, self-organized activity patterns. While the function of those spontaneous patterns of activation remains poorly understood, recent studies both in vivo and in vitro have demonstrated that neocortical neurons activate in a surprisingly similar sequential order both spontaneously and following input into cortex. For example, neurons that tend to fire earlier within spontaneous bursts of activity also fire earlier than other neurons in response to sensory stimuli. These “default patterns” can last hundreds of milliseconds and are strongly conserved under a variety of conditions. In this paper, we will review recent evidence for these default patterns at the local cortical level. We speculate that cortical architecture imposes common constraints on spontaneous and evoked activity flow, which result in the similarity of the patterns.

Scaling of Topologically Similar Functional Modules Defines Mouse Primary Auditory and Somatosensory Microcircuitry

Mapping the flow of activity through neocortical microcircuits provides key insights into the underlying circuit architecture. Using a comparative analysis we determined the extent to which the dynamics of microcircuits in mouse primary somatosensory barrel field (S1BF) and auditory (A1) neocortex generalize. We imaged the simultaneous dynamics of up to 1126 neurons spanning multiple columns and layers using high-speed multiphoton imaging. The temporal progression and reliability of reactivation of circuit events in both regions suggested common underlying cortical design features. We used circuit activity flow to generate functional connectivity maps, or graphs, to test the microcircuit hypothesis within a functional framework. S1BF and A1 present a useful test of the postulate as both regions map sensory input anatomically, but each area appears organized according to different design principles. We projected the functional topologies into anatomical space and found benchmarks of organization that had been previously described using physiology and anatomical methods, consistent with a close mapping between anatomy and functional dynamics. By comparing graphs representing activity flow we found that each region is similarly organized as highlighted by hallmarks of small world, scale free, and hierarchical modular topologies. Models of prototypical functional circuits from each area of cortex were sufficient to recapitulate experimentally observed circuit activity. Convergence to common behavior by these models was accomplished using preferential attachment to scale from an auditory up to a somatosensory circuit. These functional data imply that the microcircuit hypothesis be framed as scalable principles of neocortical circuit design.