Sensory information is processed and transmitted through the synaptic structure of local cortical... more Sensory information is processed and transmitted through the synaptic structure of local cortical circuits, but it is unclear how modulation of this architecture influences the cortical representation of sensory stimuli. Acetylcholine (ACh) promotes attention and arousal and is thought to increase the signal-to-noise ratio of sensory input in primary sensory cortices. Using high-speed two-photon calcium imaging in a thalamocortical somatosensory slice preparation, we recorded action potential activity of up to 900 neurons simultaneously and compared local cortical circuit activations with and without bath presence of ACh. We found that ACh reduced weak pairwise relationships and excluded neurons that were already unreliable during circuit activity. Using action potential activity from the imaged population, we generated functional wiring diagrams based on the statistical dependencies of activity between neurons. ACh pruned weak functional connections from spontaneous circuit activations and yielded a more modular and hierarchical circuit structure, which biased activity to flow in a more feedforward fashion. Neurons that were active in response to thalamic input had reduced pairwise dependencies overall, but strong correlations were conserved. This coincided with a prolonged period during which neurons showed temporally precise responses to thalamic input. Our results demonstrate that ACh reorganizes functional circuit structure in a manner that may enhance the integration and discriminability of thalamic afferent input within local neocortical circuitry.
Both N-methyl-D-aspartate (NMDA) and serotonin (5-HT) receptors contribute to the generation of r... more Both N-methyl-D-aspartate (NMDA) and serotonin (5-HT) receptors contribute to the generation of rhythmic motor patterns in the rat spinal cord. Co-application of these chemicals is more effective at producing locomotor-like activity than either neurochemical alone. In addition, NMDA application to rat spinal motoneurons, synaptically isolated in tetrodotoxin, induces nonlinear membrane behavior that results in voltage oscillations which can be blocked by 5-HT antagonists. However, the mechanisms underlying NMDA and 5-HT receptor interactions pertinent to motor rhythm production remain to be determined. In the present study, an in vitro neonatal rat spinal cord preparation was used to examine whether NMDA receptor-mediated nonlinear membrane voltage is modulated by 5-HT. Whole-cell recordings of spinal motoneurons demonstrated that 5-HT shifts the region of NMDA receptor-dependent negative slope conductance (RNSC) of the current-voltage relationship to more hyperpolarized potentials and enhances whole-cell inward current. The influence of 5-HT on the RNSC was similar to the effect on the RNSC of decreasing the extracellular Mg(2+)concentration. The results suggest that 5-HT may modulate this form of membrane voltage nonlinearity by regulating Mg(2+) blockade of the NMDA ionophore.
| Vertebrate spinal cord and brainstem central pattern generator (CPG) circuits share profound,si... more | Vertebrate spinal cord and brainstem central pattern generator (CPG) circuits share profound,similarities with neocortical circuits. CPGs can produce,meaningful functional output in the absence,of sensory inputs. Neocortical circuits could be considered analogous,to CPGs as they have rich spontaneous dynamics that, similar to CPGs, are powerfully modulated or engaged by sensory inputs, but can also generate output in their absence.
During the generalization of epileptic seizures, pathological activity in one brain area recruits... more During the generalization of epileptic seizures, pathological activity in one brain area recruits distant brain structures into joint synchronous discharges. However, it remains unknown whether specific changes in local circuit activity are related to the aberrant recruitment of anatomically distant structures into epileptiform discharges. Further, it is not known whether aberrant areas recruit or entrain healthy ones into pathological activity. Here we study the dynamics of local circuit activity during the spread of epileptiform discharges in the zero-magnesium in vitro model of epilepsy. We employ high-speed multi-photon imaging in combination with dual whole-cell recordings in acute thalamocortical (TC) slices of the juvenile mouse to characterize the generalization of epileptic activity between neocortex and thalamus. We find that, although both structures are exposed to zero-magnesium, the initial onset of focal epileptiform discharge occurs in cortex. This suggests that local...
Sensory information is processed and transmitted through the synaptic structure of local cortical... more Sensory information is processed and transmitted through the synaptic structure of local cortical circuits, but it is unclear how modulation of this architecture influences the cortical representation of sensory stimuli. Acetylcholine (ACh) promotes attention and arousal and is thought to increase the signal-to-noise ratio of sensory input in primary sensory cortices. Using high-speed two-photon calcium imaging in a thalamocortical somatosensory slice preparation, we recorded action potential activity of up to 900 neurons simultaneously and compared local cortical circuit activations with and without bath presence of ACh. We found that ACh reduced weak pairwise relationships and excluded neurons that were already unreliable during circuit activity. Using action potential activity from the imaged population, we generated functional wiring diagrams based on the statistical dependencies of activity between neurons. ACh pruned weak functional connections from spontaneous circuit activat...
Both N-methyl-D-aspartate (NMDA) and serotonin (5-HT) receptors contribute to the generation of r... more Both N-methyl-D-aspartate (NMDA) and serotonin (5-HT) receptors contribute to the generation of rhythmic motor patterns in the rat spinal cord. Co-application of these chemicals is more effective at producing locomotor-like activity than either neurochemical alone. In addition, NMDA application to rat spinal motoneurons, synaptically isolated in tetrodotoxin, induces nonlinear membrane behavior that results in voltage oscillations which can be blocked by 5-HT antagonists. However, the mechanisms underlying NMDA and 5-HT receptor interactions pertinent to motor rhythm production remain to be determined. In the present study, an in vitro neonatal rat spinal cord preparation was used to examine whether NMDA receptor-mediated nonlinear membrane voltage is modulated by 5-HT. Whole-cell recordings of spinal motoneurons demonstrated that 5-HT shifts the region of NMDA receptor-dependent negative slope conductance (RNSC) of the current-voltage relationship to more hyperpolarized potentials ...
The effect of serotonin (5-HT) receptor blockade on rhythmic network activity and on N-methyl--as... more The effect of serotonin (5-HT) receptor blockade on rhythmic network activity and on N-methyl--aspartate (NMDA) receptor-induced membrane voltage oscillations was examined using an in vitro neonatal rat spinal cord preparation. Pharmacologically induced rhythmic hindlimb activity, monitored via flexor and extensor electroneurograms or ventral root recordings, was abolished by 5-HT receptor antagonists. Intrinsic motoneuronal voltage oscillations, induced by NMDA in the presence of tetrodotoxin (TTX), either were abolished completely or transformed to long-lasting voltage shifts by 5-HT receptor antagonists. Conversely, 5-HT application facilitated the expression of NMDA-receptor-mediated rhythmic voltage oscillations. The results suggest that an interplay between 5-HT and NMDA receptor actions may be critical for the production of rhythmic motor behavior in the mammalian spinal cord, both at the network and single cell level.
Correlations in local neocortical spiking activity can provide insight into the underlying organi... more Correlations in local neocortical spiking activity can provide insight into the underlying organization of cortical microcircuitry. However, identifying structure in patterned multi-neuronal spiking remains a daunting task due to the high dimensionality of the activity. Using two-photon imaging, we monitored spontaneous circuit dynamics in large, densely sampled neuronal populations within slices of mouse primary auditory, somatosensory, and visual cortex. Using the lagged correlation of spiking activity between neurons, we generated functional wiring diagrams to gain insight into the underlying neocortical circuitry. By establishing the presence of graph invariants, which are label-independent characteristics common to all circuit topologies, our study revealed organizational features that generalized across functionally distinct cortical regions. Regardless of sensory area, random and k-nearest neighbors null graphs failed to capture the structure of experimentally derived functional circuitry. These null models indicated that despite a bias in the data towards spatially proximal functional connections, functional circuit structure is best described by non-random and occasionally distal connections. Eigenvector centrality, which quantifies the importance of a neuron in the temporal flow of circuit activity, was highly related to feedforwardness in all functional circuits. The number of nodes participating in a functional circuit did not scale with the number of neurons imaged regardless of sensory area, indicating that circuit size is not tied to the sampling of neocortex. Local circuit flow comprehensively covered angular space regardless of the spatial scale that we tested, demonstrating that circuitry itself does not bias activity flow toward pia. Finally, analysis revealed that a minimal numerical sample size of neurons was necessary to capture at least 90 percent of functional circuit topology. These data and analyses indicated that functional circuitry exhibited rules of organization which generalized across three areas of sensory neocortex.
Mapping the flow of activity through neocortical microcircuits provides key insights into the und... more 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.
Sensory information is processed and transmitted through the synaptic structure of local cortical... more Sensory information is processed and transmitted through the synaptic structure of local cortical circuits, but it is unclear how modulation of this architecture influences the cortical representation of sensory stimuli. Acetylcholine (ACh) promotes attention and arousal and is thought to increase the signal-to-noise ratio of sensory input in primary sensory cortices. Using high-speed two-photon calcium imaging in a thalamocortical somatosensory slice preparation, we recorded action potential activity of up to 900 neurons simultaneously and compared local cortical circuit activations with and without bath presence of ACh. We found that ACh reduced weak pairwise relationships and excluded neurons that were already unreliable during circuit activity. Using action potential activity from the imaged population, we generated functional wiring diagrams based on the statistical dependencies of activity between neurons. ACh pruned weak functional connections from spontaneous circuit activations and yielded a more modular and hierarchical circuit structure, which biased activity to flow in a more feedforward fashion. Neurons that were active in response to thalamic input had reduced pairwise dependencies overall, but strong correlations were conserved. This coincided with a prolonged period during which neurons showed temporally precise responses to thalamic input. Our results demonstrate that ACh reorganizes functional circuit structure in a manner that may enhance the integration and discriminability of thalamic afferent input within local neocortical circuitry.
Both N-methyl-D-aspartate (NMDA) and serotonin (5-HT) receptors contribute to the generation of r... more Both N-methyl-D-aspartate (NMDA) and serotonin (5-HT) receptors contribute to the generation of rhythmic motor patterns in the rat spinal cord. Co-application of these chemicals is more effective at producing locomotor-like activity than either neurochemical alone. In addition, NMDA application to rat spinal motoneurons, synaptically isolated in tetrodotoxin, induces nonlinear membrane behavior that results in voltage oscillations which can be blocked by 5-HT antagonists. However, the mechanisms underlying NMDA and 5-HT receptor interactions pertinent to motor rhythm production remain to be determined. In the present study, an in vitro neonatal rat spinal cord preparation was used to examine whether NMDA receptor-mediated nonlinear membrane voltage is modulated by 5-HT. Whole-cell recordings of spinal motoneurons demonstrated that 5-HT shifts the region of NMDA receptor-dependent negative slope conductance (RNSC) of the current-voltage relationship to more hyperpolarized potentials and enhances whole-cell inward current. The influence of 5-HT on the RNSC was similar to the effect on the RNSC of decreasing the extracellular Mg(2+)concentration. The results suggest that 5-HT may modulate this form of membrane voltage nonlinearity by regulating Mg(2+) blockade of the NMDA ionophore.
| Vertebrate spinal cord and brainstem central pattern generator (CPG) circuits share profound,si... more | Vertebrate spinal cord and brainstem central pattern generator (CPG) circuits share profound,similarities with neocortical circuits. CPGs can produce,meaningful functional output in the absence,of sensory inputs. Neocortical circuits could be considered analogous,to CPGs as they have rich spontaneous dynamics that, similar to CPGs, are powerfully modulated or engaged by sensory inputs, but can also generate output in their absence.
During the generalization of epileptic seizures, pathological activity in one brain area recruits... more During the generalization of epileptic seizures, pathological activity in one brain area recruits distant brain structures into joint synchronous discharges. However, it remains unknown whether specific changes in local circuit activity are related to the aberrant recruitment of anatomically distant structures into epileptiform discharges. Further, it is not known whether aberrant areas recruit or entrain healthy ones into pathological activity. Here we study the dynamics of local circuit activity during the spread of epileptiform discharges in the zero-magnesium in vitro model of epilepsy. We employ high-speed multi-photon imaging in combination with dual whole-cell recordings in acute thalamocortical (TC) slices of the juvenile mouse to characterize the generalization of epileptic activity between neocortex and thalamus. We find that, although both structures are exposed to zero-magnesium, the initial onset of focal epileptiform discharge occurs in cortex. This suggests that local...
Sensory information is processed and transmitted through the synaptic structure of local cortical... more Sensory information is processed and transmitted through the synaptic structure of local cortical circuits, but it is unclear how modulation of this architecture influences the cortical representation of sensory stimuli. Acetylcholine (ACh) promotes attention and arousal and is thought to increase the signal-to-noise ratio of sensory input in primary sensory cortices. Using high-speed two-photon calcium imaging in a thalamocortical somatosensory slice preparation, we recorded action potential activity of up to 900 neurons simultaneously and compared local cortical circuit activations with and without bath presence of ACh. We found that ACh reduced weak pairwise relationships and excluded neurons that were already unreliable during circuit activity. Using action potential activity from the imaged population, we generated functional wiring diagrams based on the statistical dependencies of activity between neurons. ACh pruned weak functional connections from spontaneous circuit activat...
Both N-methyl-D-aspartate (NMDA) and serotonin (5-HT) receptors contribute to the generation of r... more Both N-methyl-D-aspartate (NMDA) and serotonin (5-HT) receptors contribute to the generation of rhythmic motor patterns in the rat spinal cord. Co-application of these chemicals is more effective at producing locomotor-like activity than either neurochemical alone. In addition, NMDA application to rat spinal motoneurons, synaptically isolated in tetrodotoxin, induces nonlinear membrane behavior that results in voltage oscillations which can be blocked by 5-HT antagonists. However, the mechanisms underlying NMDA and 5-HT receptor interactions pertinent to motor rhythm production remain to be determined. In the present study, an in vitro neonatal rat spinal cord preparation was used to examine whether NMDA receptor-mediated nonlinear membrane voltage is modulated by 5-HT. Whole-cell recordings of spinal motoneurons demonstrated that 5-HT shifts the region of NMDA receptor-dependent negative slope conductance (RNSC) of the current-voltage relationship to more hyperpolarized potentials ...
The effect of serotonin (5-HT) receptor blockade on rhythmic network activity and on N-methyl--as... more The effect of serotonin (5-HT) receptor blockade on rhythmic network activity and on N-methyl--aspartate (NMDA) receptor-induced membrane voltage oscillations was examined using an in vitro neonatal rat spinal cord preparation. Pharmacologically induced rhythmic hindlimb activity, monitored via flexor and extensor electroneurograms or ventral root recordings, was abolished by 5-HT receptor antagonists. Intrinsic motoneuronal voltage oscillations, induced by NMDA in the presence of tetrodotoxin (TTX), either were abolished completely or transformed to long-lasting voltage shifts by 5-HT receptor antagonists. Conversely, 5-HT application facilitated the expression of NMDA-receptor-mediated rhythmic voltage oscillations. The results suggest that an interplay between 5-HT and NMDA receptor actions may be critical for the production of rhythmic motor behavior in the mammalian spinal cord, both at the network and single cell level.
Correlations in local neocortical spiking activity can provide insight into the underlying organi... more Correlations in local neocortical spiking activity can provide insight into the underlying organization of cortical microcircuitry. However, identifying structure in patterned multi-neuronal spiking remains a daunting task due to the high dimensionality of the activity. Using two-photon imaging, we monitored spontaneous circuit dynamics in large, densely sampled neuronal populations within slices of mouse primary auditory, somatosensory, and visual cortex. Using the lagged correlation of spiking activity between neurons, we generated functional wiring diagrams to gain insight into the underlying neocortical circuitry. By establishing the presence of graph invariants, which are label-independent characteristics common to all circuit topologies, our study revealed organizational features that generalized across functionally distinct cortical regions. Regardless of sensory area, random and k-nearest neighbors null graphs failed to capture the structure of experimentally derived functional circuitry. These null models indicated that despite a bias in the data towards spatially proximal functional connections, functional circuit structure is best described by non-random and occasionally distal connections. Eigenvector centrality, which quantifies the importance of a neuron in the temporal flow of circuit activity, was highly related to feedforwardness in all functional circuits. The number of nodes participating in a functional circuit did not scale with the number of neurons imaged regardless of sensory area, indicating that circuit size is not tied to the sampling of neocortex. Local circuit flow comprehensively covered angular space regardless of the spatial scale that we tested, demonstrating that circuitry itself does not bias activity flow toward pia. Finally, analysis revealed that a minimal numerical sample size of neurons was necessary to capture at least 90 percent of functional circuit topology. These data and analyses indicated that functional circuitry exhibited rules of organization which generalized across three areas of sensory neocortex.
Mapping the flow of activity through neocortical microcircuits provides key insights into the und... more 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.
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