Cortical amplification models of experience-dependent development of selective columns and response sparsification.

The development of direction-selective cortical columns requires visual experience, but the neural circuits and plasticity mechanisms that are responsible for this developmental transition are unknown. To gain insight into the mechanisms that could underlie experience-dependent increases in selectivity, we explored families of cortical amplifier models that enhance weakly biased feedforward signals. Here we focused exclusively on possible contributions of cortico-cortical connections and took feedforward input to be constant. We modeled pairs of interconnected columns that received equal and oppositely biased inputs. In a single-element model of cortical columns, we found two ways that cortical columns could receive biased feedforward input and exhibit strong but unselective responses to stimuli: 1) within-column recurrent excitatory connections could be strong enough to amplify both strong and weak feedforward input, or 2) columns that received differently biased inputs could have strong excitatory cross-connections that destroy selectivity. A Hebbian plasticity rule combined with simulated experience with stimuli weakened these strong cross-connections across cortical columns, allowing the individual columns to respond selectively to their biased inputs. In a model that included both excitatory and inhibitory neurons in each column, an additional means of obtaining selectivity through the cortical circuit was uncovered: cross-column suppression of inhibition-stabilized networks. When each column operated as an inhibition-stabilized network, cross-column excitation onto inhibitory neurons forced competition between the columns but in a manner that did not involve strong null-direction inhibition, consistent with experimental measurements of direction selectivity in visual cortex. Experimental predictions of these possible contributions of cortical circuits are discussed.NEW & NOTEWORTHY Sensory circuits are initially constructed via mechanisms that are independent of sensory experience, but later refinement requires experience. We constructed models of how circuits that receive biased feedforward inputs can be initially unselective and then be modified by experience and plasticity so that the resulting circuit exhibits increased selectivity. We propose that neighboring cortical columns may initially exhibit coupling that is too strong for selectivity. Experience-dependent mechanisms decrease this coupling so individual columns can exhibit selectivity.

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.

Spectral breadth and laminar distribution of thalamocortical inputs to A1.

The GABAergic agonist muscimol is used to inactivate brain regions in order to reveal afferent inputs in isolation. However, muscimol's use in primary auditory cortex (A1) has been questioned on the grounds that it may unintentionally suppress thalamocortical inputs. We tested whether muscimol can preferentially suppress cortical, but not thalamocortical, circuits in urethane-anesthetized mice. We recorded tone-evoked current source density profiles to determine frequency receptive fields (RFs) for three current sinks: the "layer 4" sink (fastest onset, middle-layer sink) and current sinks 100 µm above ("layer 2/3") and 300 µm below ("layer 5/6") the main input. We first determined effects of muscimol dose (0.01-1 mM) on the characteristic frequency (CF) tone-evoked layer 4 sink. An "ideal" dose (100 µM) had no effect on CF-evoked sink onset latency or initial response but reduced peak amplitude by >80%, implying inhibition of intracortical, but not thalamocortical, activity. We extended the analysis to current sinks in layers 2/3 and 5/6 and for all three sinks determined RF breadth (quarter-octave steps, 20 dB above CF threshold). Muscimol reduced RF breadth 42% in layer 2/3 (from 2.4 ± 0.14 to 1.4 ± 0.11 octaves), 14% in layer 4 (2.2 ± 0.12 to 1.9 ± 0.10 octaves), and not at all in layer 5/6 (1.8 ± 0.10 to 1.7 ± 0.12 octaves). The results provide an estimate of the laminar and spectral extent of thalamocortical projections and support the hypothesis that intracortical pathways contribute to spectral integration in A1.

Stem cell restores thalamocortical plasticity to rescue cognitive deficit in neonatal intraventricular hemorrhage.

Severe neonatal intraventricular hemorrhage (IVH) patients incur long-term neurologic deficits such as cognitive disabilities. Recently, the intraventricular transplantation of allogeneic human umbilical cord blood-derived mesenchymal stem cells (MSCs) has drawn attention as a therapeutic potential to treat severe IVH. However, its pathological synaptic mechanism is still elusive. We here demonstrated that the integration of the somatosensory input was significantly distorted by suppressing feed-forward inhibition (FFI) at the thalamocortical (TC) inputs in the barrel cortices of neonatal rats with IVH by using BOLD-fMRI signal and brain slice patch-clamp technique. This is induced by the suppression of Hebbian plasticity via an increase in tumor necrosis factor-α expression during the critical period, which can be effectively reversed by the transplantation of MSCs. Furthermore, we showed that MSC transplantation successfully rescued IVH-induced learning deficits in the sensory-guided decision-making in correlation with TC FFI in the layer 4 barrel cortex.

The organization and development of cortical interneuron presynaptic circuits are area specific.

Parvalbumin and somatostatin inhibitory interneurons gate information flow in discrete cortical areas that compute sensory and cognitive functions. Despite the considerable differences between areas, individual interneuron subtypes are genetically invariant and are thought to form canonical circuits regardless of which area they are embedded in. Here, we investigate whether this is achieved through selective and systematic variations in their afferent connectivity during development. To this end, we examined the development of their inputs within distinct cortical areas. We find that interneuron afferents show little evidence of being globally stereotyped. Rather, each subtype displays characteristic regional connectivity and distinct developmental dynamics by which this connectivity is achieved. Moreover, afferents dynamically regulated during development are disrupted by early sensory deprivation and in a model of fragile X syndrome. These data provide a comprehensive map of interneuron afferents across cortical areas and reveal the logic by which these circuits are established during development.