Cortical information processing is under state-dependent control of subcortical neuromodulatory
systems. Although this modulatory effect is thought to be mediated mainly by slow
nonsynaptic metabotropic receptors, other mechanisms, such as direct synaptic transmission,
are possible. Yet, it is currently unknown if any such form of subcortical control
exists. Here, we present direct evidence of a strong, spatiotemporally precise excitatory
input from an ascending neuromodulatory center. Selective stimulation of serotonergic
median raphe neurons produced a rapid activation of hippocampal interneurons. At the
network level, this subcortical drive was manifested as a pattern of effective disynaptic
GABAergic inhibition that spread throughout the circuit. This form of subcortical
network regulation should be incorporated into current concepts of normal and pathological
cortical function.
