Yoshifumi Ueta

Differentiated Participation of Thalamocortical Subnetworks in Slow/Spindle Waves and Desynchronization

During sleep, the electroencephalogram exhibits synchronized slow waves that desynchronize when animals awaken [desynchronized states (DSs)]. During slow-wave states, the membrane potentials of cortical neurons oscillate between discrete depolarized states (“Up states”) and periods of hyperpolarization (“Down states”). To determine the role of corticothalamic loops in generating Up/Down oscillations in rats, we recorded unit activities of layer 5 (L5) corticothalamic (CTh) cells in the frontal cortex, neurons in the thalamic reticular nucleus, and basal ganglia- and cerebellum-linked thalamic relay nuclei, while simultaneously monitoring the local cortical field potential to identify slow-wave/spindle oscillations and desynchronization. We found that (1) some basal ganglia-linked and reticular thalamic cells fire preferentially near the beginning of Up states; (2) thalamic cells fire more selectively at a given Up-state phase than do CTh cells; (3) CTh and thalamic cells exhibit different action potential timings within spindle cycles; and (4) neurons exhibit different firing characteristics when comparing their activity during Up states and DSs. These data demonstrate that cortico-thalamo-cortical subnetworks are temporally differentiated during slow and spindle oscillations, that the basal ganglia-linked thalamic nuclei are closely related with Up-state initiation, and that Up states and DSs are distinguished as different depolarization states of neurons within the network.

Direction- and distance-dependent interareal connectivity of pyramidal cell subpopulations in the rat frontal cortex

The frontal cortex plays an important role in the initiation and execution of movements via widespread projections to various cortical and subcortical areas. Layer 2/3 (L2/3) pyramidal cells in the frontal cortex send axons mainly to other ipsilateral/contralateral cortical areas. Subpopulations of layer 5 (L5) pyramidal cells that selectively project to the pontine nuclei or to the contralateral cortex [commissural (COM) cells] also target diverse and sometimes overlapping ipsilateral cortical areas. However, little is known about target area-dependent participation in ipsilateral corticocortical (iCC) connections by subclasses of L2/3 and L5 projection neurons. To better understand the functional hierarchy between cortical areas, we compared iCC connectivity between the secondary motor cortex (M2) and adjacent areas, such as the orbitofrontal and primary motor cortices, and distant non-frontal areas, such as the perirhinal and posterior parietal cortices. We particularly assessed the laminar distribution of iCC cells and fibers, and identified the subtypes of pyramidal cells participating in those projections. For connections between M2 and frontal areas, L2/3 and L5 cells in both areas contributed to reciprocal projections, which can be viewed as “bottom-up” or “top-down” on the basis of their differential targeting of cortical lamina. In connections between M2 and non-frontal areas, neurons participating in bottom-up and top-down projections were segregated into the different layers: bottom-up projections arose primarily from L2/3 cells, while top-down projections were dominated by L5 COM cells. These findings suggest that selective participation in iCC connections by pyramidal cell subtypes lead to directional connectivity between M2 and other cortical areas. Based on these findings, we propose a provisional unified framework of interareal hierarchy within the frontal cortex, and discuss the interaction of local circuits with long-range interareal connections.

Suppression of a Neocortical Potassium Channel Activity by Intracellular Amyloid-β and Its Rescue with Homer1a

It is proposed that intracellular amyloid-β (Aβ), before extracellular plaque formation, triggers cognitive deficits in Alzheimer disease (AD). Here we report how intracellular Aβ affects neuronal properties. This was done by injecting Aβ protein into rat and mouse neocortical pyramidal cells through whole-cell patch pipettes and by using 3xTg AD model mice, in which intracellular Aβ is accumulated innately. In rats, intracellular application of a mixed Aβ1-42 preparation containing both oligomers and monomers, but not a monomeric preparation of Aβ1-40, broadened spike width and augmented Ca2+ influx via voltage-dependent Ca2+ channels in neocortical neurons. Both effects were mimicked and occluded by charybdotoxin, a blocker of large-conductance Ca2+-activated K+ (BK) channels, and blocked by isopimaric acid, a BK channel opener. Surprisingly, augmented Ca2+ influx was caused by elongated spike duration, but not attributable to direct Ca2+ channel modulation by Aβ1-42. The Aβ1-42-induced spike broadening was blocked by electroconvulsive shock (ECS), which we previously showed to facilitate BK channel opening via expression of the scaffold protein Homer1a. In young 3xTg and wild mice, we confirmed spike broadening by Aβ1-42, which was again mimicked and occluded by charybdotoxin and blocked by ECS. In Homer1a knock-out mice, ECS failed to block the Aβ1-42 effect. Single-channel recording on BK channels supported these results. These findings suggest that the suppression of BK channels by intracellular Aβ1-42 is a possible key mechanism for early dysfunction in the AD brain, which may be counteracted by activity-dependent expression of Homer1a.

Selective Thalamic Innervation of Rat Frontal Cortical Neurons

Most glutamatergic inputs in the neocortex originate from the thalamus or neocortical pyramidal cells. To test whether thalamocortical afferents selectively innervate specific cortical cell subtypes and surface domains, we investigated the distribution patterns of thalamocortical and corticocortical excitatory synaptic inputs in identified postsynaptic cortical cell subtypes using intracellular and immunohistochemical staining combined with confocal laser scanning and electron microscopic observations in 2 thalamorecipient sublayers, lower layer 2/3 (L2/3b) and lower layer 5 (L5b) of rat frontal cortex. The dendrites of GABAergic parvalbumin (PV) cells preferentially received corticocortical inputs in both sublayers. The somata of L2/3b PV cells received thalamic inputs in similar proportions to the basal dendritic spines of L2/3b pyramidal cells, whereas L5b PV somata were mostly innervated by cortical inputs. The basal dendrites of L2/3b pyramidal and L5b corticopontine pyramidal cells received cortical and thalamic glutamatergic inputs in proportion to their local abundance, whereas crossed-corticostriatal pyramidal cells in L5b exhibited a preference for thalamic inputs, particularly in their distal dendrites. Our data demonstrate an exquisite selectivity among thalamocortical afferents in which synaptic connectivity is dependent on the postsynaptic neuron subtype, cortical sublayer, and cell surface domain.

A serotonergic discrimination favoring synaptic inputs that accompany robust spike firing in lateral amygdala neurons

The amygdala and serotonergic innervations thereunto are considered to cooperatively modulate affective behaviors. By whole-cell recording, the present study examined effects of serotonin (5-HT) on synaptic transmission in the rat basolateral amygdala (BLA) complex, which is the amygdalar entrance for sensory information. Application of 5-HT-attenuated excitatory postsynaptic currents at synapses from the lateral amygdala (LA) to the BLA proper, and also at synapses from putative thalamic afferents to LA principal neurons, both depending on 5-HT(2) receptors. This reduction of synaptic responses was confirmed in the BLA under current clamp. In the LA, by contrast, synaptic potentials were not reduced, but enhanced by 5-HT. With 5-HT bath-applied, a prolonged depolarization was induced in LA neurons by strong synaptic stimulation, which appears similar to a slow after-depolarization (sADP) induced by injecting depolarizing currents. Occurrence of such current-induced sADP was confirmed in LA neurons. Both the synaptically-activated prolonged depolarization and the current-induced sADPs depended on 5-HT(2) receptor activation and postsynaptic calcium increase, suggesting that the same postsynaptic intrinsic mechanisms are involved. Reduction of potassium currents was identified as a major ionic mechanism for this sADPs. We thus revealed that 5-HT usually reduces overall synaptic transmission in the whole BLA complex, but enables sADPs to occur, thereby increasing synaptic responsiveness of LA neurons in a positive feedback manner. With this duality of 5-HT actions in operation, a weak input to the BLA complex would be usually eliminated, but could be selected were it associated with sufficiently large depolarization.

Electroconvulsive stimulation blocks intracellular amyloid-β-mediated suppression of BK channels in a homer 1a/vesl-1S-dependent mechanism

Family structure around a child is one of the strongest environmental factors for his/her social and mental development. To investigate how the behavioral traits of juvenile primate represent human development, we prepared three groups of subjects different in their family structure, that is, bred without other siblings, either by human (H1) or by its own parents (P1), and with another sibling by its own parents (P2). We evaluated their behavioral development in our original meeting test between two or four peers. The multivariate analysis of the test result expressed the different behavioral patterns more distinctly at the contexts in 4 peers than 2. Interestingly, P1’s pattern showed the least change from 2to 4-peer-context, comparing to H1’s or P2’s. These results suggest that social brain function was sculpted through social interaction between parent–child and peers during development.