Intracellular analysis of the synaptic inputs to neocortical neurons using in vitro slice preparations of the primary somatosensory neocortex of rats reveals the most distal layer I dendrites of pyramidal neurons are surprisingly sensitive (Cauller and Connors, 1992; 1994). These studies employ a novel slice preparation which isolates the horizontal fibers in layer I (HLI) with a cut through deeper layers. Fiber tracing experiments (see Neuroanatomy Project) have demonstrated that a large portion of these horizontal fibers in layer I are backward projections originating in higher cortical areas. The isolated HLI slice provides a unique way to study a specific input to cortical neurons restricted to a known portion of the dendritic tree. The synaptic response to these distal HLI inputs recorded in pyramidal neurons consists of a monophasic depolarizing potential lasting at least 50 ms which grows with stimulus intensity to evoke a burst of action potentials. In contrast, the synaptic response to thalamocortical or other inputs to middle layers consists of a brief EPSP trucated by a multiphasic IPSP lasting up to 100 ms. This study has demonstrated that the inhibitory phase of the middle layer inputs attenuates the distal HLI response apparently by shunting along the apical trunk. By filling neurons with biocytin, the study demonstrated that only pyramidal neurons in layers II/III and V with distal apical dendrites in layer I responded to the HLI stimulus (non-spiny stellates, layer IV spiny stellates, and layer VI pyramidal neurons did not respond to HLI inputs). The intrinsically bursting pyramidal neurons in layer V were especially sensitive to HLI inputs. Subsequent studies using the HLI slice have demonstrated the response to distal synaptic inputs is modulated by nicotinic cholinergic agonists (Li and Cauller, 1997). In summary, these studies have demonstrated the backward inputs to layer I which are the most likely source of activation for the behaviorally relevant N1 response (see Neural Correlates Project), powerfully excite a subset of cortical pyramidal neurons including the corticobulbar projections (see Neuroanatomy Project).