Monosynaptic connections between pairs of spiny stellate cells in layer 4 and pyramidal cells in layer 5A indicate that lemniscal and paralemniscal afferent pathways converge in the infragranular somatosensory cortex.

Monosynaptic interlaminar connections between spiny stellate cells in layer 4 (L4), the main cortical recipient layer for thalamic projections, and pyramidal cells in layer 5A (L5A), one of the main cortical output layers, were examined anatomically and functionally by paired recordings in acute brain slices. The somata of pairs forming interlaminar L4-to-L5A connections were located predominantly close to or directly under the barrel-septum wall in layer 4. Superposition of spiny stellate axon arbors and L5A pyramidal cell dendritic arbors suggested an innervation domain underneath an L4 barrel wall. Functionally, the L4-to-L5A connections were of high reliability and relatively low efficacy, with a unitary EPSP amplitude of 0.6 mV, and the connectivity was moderately high (one in seven pairs tested was connected). The EPSP amplitude was weakly depressing (paired-pulse ratio of approximately 0.8) during repetitive presynaptic action potentials at 10 Hz. The existence of Monosynaptic L4-to-L5A connections indicates that the specific 'lemniscal' thalamic input from the ventro-basal nucleus of the thalamus to the cortex and the more unspecific 'paralemniscal' afferent thalamic projections from the posterior medial nucleus of the thalamus merge already at an initial stage of cortical signal processing. These Monosynaptic connections establish a Monosynaptic coupling of the input to the cortex and its output, thereby effectively bypassing the supragranular layers

A laminar organization for selective cortico-cortical communication

The neocortex is central to mammalian cognitive ability, playing critical roles in sensory perception, motor skills and executive function. This thin, layered structure comprises distinct, functionally specialized areas that communicate with each other through the axons of pyramidal neurons. For the hundreds of such cortico-cortical pathways to underlie diverse functions, their cellular and synaptic architectures must differ so that they result in distinct computations at the target projection neurons. In what ways do these pathways differ? By originating and terminating in different laminae, and by selectively targeting specific populations of excitatory and inhibitory neurons, these “interareal” pathways can differentially control the timing and strength of synaptic inputs onto individual neurons, resulting in layer-specific computations. Due to the rapid development in transgenic techniques, the mouse has emerged as a powerful mammalian model for understanding the rules by which cortical circuits organize and function. Here we review our understanding of how cortical lamination constrains long-range communication in the mammalian brain, with an emphasis on the mouse visual cortical network. We discuss the laminar architecture underlying interareal communication, the role of neocortical layers in organizing the balance of excitatory and inhibitory actions, and highlight the structure and function of layer 1 in mouse visual cortex

In vivo measurement of afferent activity with axon-specific calcium imaging.

In vivo calcium imaging from axons provides direct interrogation of afferent neural activity, informing the neural representations that a local circuit receives. Unlike in somata and dendrites, axonal recording of neural activity-both electrically and optically-has been difficult to achieve, thus preventing comprehensive understanding of neuronal circuit function. Here we developed an active transportation strategy to enrich GCaMP6, a genetically encoded calcium indicator, uniformly in axons with sufficient brightness, signal-to-noise ratio, and photostability to allow robust, structure-specific imaging of presynaptic activity in awake mice. Axon-targeted GCaMP6 enables frame-to-frame correlation for motion correction in axons and permits subcellular-resolution recording of axonal activity in previously inaccessible deep-brain areas. We used axon-targeted GCaMP6 to record layer-specific local afferents without contamination from somata or from intermingled dendrites in the cortex. We expect that axon-targeted GCaMP6 will facilitate new applications in investigating afferent signals relayed by genetically defined neuronal populations within and across specific brain regions

Circuit Development in the Dorsal Lateral Geniculate Nucleus (dLGN) of the Mouse.

The visual system is one of the most widely used and best understood sensory systems and the dorsal lateral geniculate nucleus (dLGN) of the mouse has emerged as a model for investigating the cellular and molecular mechanisms underlying the development and activity-dependent refinement of sensory connections. Thalamic organization is highly conserved throughout species and the dLGN of the mouse possesses many features common to higher mammals, such as carnivores and primates. Two general classes of neuron are present within the dLGN, thalamocortical relay cells and interneurons, both of which receive direct retinal input. Axons of relay cells exit dLGN and convey visual information to layer IV of cortex, whereas interneurons are involved in local circuitry. In addition, dLGN receives rich nonretinal input from numerous areas of the brain. Studies thus far have focused on the retinogeniculate pathway and the development of connections between retinal ganglion cells (RGCs) and relay cells has been well characterized. However, there are still a number of unanswered questions about circuit development in dLGN. Here we examined two aspects that are not well understood, the pattern of retinal convergence onto interneurons and the structural and functional innervation of nonretinal projections. To address the first issue we conducted in vitro whole-cell recordings from acute thalamic slices of GAD67-GFP mice, a transgenic strain in which dLGN interneurons express GFP. We also did 3-D reconstructions of biocytin-labeled interneurons using multi-photon laser scanning microscopy in conjunction with anterograde labeling of retinogeniculate projections to examine the distribution of retinal contacts. To begin to examine the development of nonretinal connections in dLGN we made use of a transgenic mouse (golli-τ-GFP) to visualize corticogeniculate projections, one of the largest sources of nonretinal input to dLGN. Using this mouse we studied the timing and patterning of corticogeniculate innervation in relation to the development of the retinogeniculate pathway. We also used binocular enucleation and genetic deafferentation to test whether the retina plays a role in regulating nonretinal innervation. We found that there is a coordination of retinal and nonretinal innervation in dLGN. Projections from the retina were the first to innervate and they entered dLGN at perinatal ages. They also made functional connections with both relay cells and interneurons at early postnatal ages. Interestingly, relay cells underwent a period of retinogeniculate refinement, whereas the degree of retinal convergence onto interneurons was maintained. This possibly reflects the different roles that these two cell types have in dLGN. Both structural and functional corticogeniculate innervation was delayed in comparison and occurred postnatally, however in the absence of retinal input the timing of corticogeniculate innervation was accelerated. RGCs transmit the visual information encoded in the retina to dLGN so it may be necessary for these connections to be formed before those from nonretinal projections, which serve to modulate that signal on its way to cortex. Thus precise timing of retinal and nonretinal innervation may be important for the appropriate formation of connections in the visual system and the retina seems to be playing an important role in regulating this timing

Motor Learning Mechanism on the Neuron Scale

Based on existing data, we wish to put forward a biological model of motor system on the neuron scale. Then we indicate its implications in statistics and learning. Specifically, neuron firing frequency and synaptic strength are probability estimates in essence. And the lateral inhibition also has statistical implications. From the standpoint of learning, dendritic competition through retrograde messengers is the foundation of conditional reflex and grandmother cell coding. And they are the kernel mechanisms of motor learning and sensory motor integration respectively. Finally, we compare motor system with sensory system. In short, we would like to bridge the gap between molecule evidences and computational models.Comment: 8 pages, 4 figure

Thalamic Inhibition: Diverse Sources, Diverse Scales.

The thalamus is the major source of cortical inputs shaping sensation, action, and cognition. Thalamic circuits are targeted by two major inhibitory systems: the thalamic reticular nucleus (TRN) and extrathalamic inhibitory (ETI) inputs. A unifying framework of how these systems operate is currently lacking. Here, we propose that TRN circuits are specialized to exert thalamic control at different spatiotemporal scales. Local inhibition of thalamic spike rates prevails during attentional selection, whereas global inhibition more likely prevails during sleep. In contrast, the ETI (arising from basal ganglia, zona incerta (ZI), anterior pretectum, and pontine reticular formation) provides temporally precise and focal inhibition, impacting spike timing. Together, these inhibitory systems allow graded control of thalamic output, enabling thalamocortical operations to dynamically match ongoing behavioral demands

Effects of Adaptation in a Somatosensory Thalamocortical Circuit

In the mammalian brain, thalamocortical circuits perform the initial stage of processing before information is sent to higher levels of the cerebral cortex. Substantial changes in receptive field properties are produced in the thalamocortical response transformation. In the whisker-to-barrel thalamocortical pathway, the response magnitude of barrel excitatory cells is sensitive to the velocity of whisker deflections, whereas in the thalamus, velocity is only encoded by firing synchrony. The behavior of this circuit can be captured in a model which contains a window of opportunity for thalamic firing synchrony to engage intra-barrel recurrent excitation before being 'damped' by slightly delayed, but strong, local feedforward inhibition. Some remaining aspects of the model that require investigation are: (1) how does adaptation with ongoing and repetitive sensory stimulation affect processing in this circuit and (2) what are the rules governing intra-barrel interactions. By examining sensory processing in thalamic barreloids and cortical barrels, before and after adaptation with repetitive high-frequency whisker stimulation, I have determined that adaptation modifies the operations of the thalamocortical circuit without fundamentally changing it. In the non-adapted state, higher velocities produce larger responses in barrel cells than lower velocities. Similarly, in the adapted barrel, putative excitatory and inhibitory neurons can respond with temporal fidelity to high-frequency whisker deflections if they are of sufficient velocity. Additionally, before and after adaptation, relative to putative excitatory cells, inhibitory cells produce larger responses and are more broadly-tuned for stimulus parameters (e.g., the angle of whisker deflection). In barrel excitatory cells, adaptation is angularly-nonspecific; that is, response suppression is not specific to the angle of the adapting stimulus. The angular tuning of barrel excitatory cells is sharpened and the original angular preference is maintained. This is consistent with intra-barrel interactions being angularly-nonspecific. The maintenance of the original angular preference also suggests that the same thalamocortical inputs determine angular tuning before and after adaptation. In summary, the present findings suggest that adaptation narrows the window of opportunity for synchronous thalamic inputs to engage recurrent excitation so that it can withstand strong, local inhibition. These results from the whisker-to-barrel thalamocortical response transformation are likely to have parallels in other systems