Neural circuit regulation of prepulse inhibition of startle in the rat: current knowledge and future challenges

Rationale: Sensorimotor gating of the startle reflex can be assessed across species, using similar stimuli to elicit similar responses. Prepulse inhibition (PPI), a measure of sensorimotor gating, is reduced in patients with some neuropsychiatric disorders, and in rats after manipulations of limbic cortex. striatum, pallidum or pontine tegmentum ("CSPP" circuitry). Objective: To review the current knowledge of the neural circuit regulation of PPI in rats, and to anticipate the future challenges facing this line of inquiry. Methods: The published literature was reviewed and critically evaluated. Results: Limbic CSPP circuitry has been studied in rats to reveal the neurochemical and neuroanatomical substrates regulating PPI at a high level of resolution. In translational cross-species research, this detailed circuit information is used as a "blueprint" to identify substrates that may lead to PPI deficits in psychiatrically disordered humans. Some human disorders with identifiable, localized lesions in CSPP circuitry may provide direct validation for the contribution of CSPP circuitry to this cross-species model. The rapid collection of experimental data supporting this cross-species PPI circuit "blueprint" has supported continuing advances in the development of theoretical models for understanding how this circuitry normally functions to regulate PPI. Such models are needed for building a conceptual framework for understanding the role of this circuitry in the regulation of sensorimotor gating in normal humans, and in the relative loss of sensorimotor gating, and the resulting clinical consequences, in individuals with particular neuropsychiatric disorders. Conclusions: Our understanding of the neural regulation of PPI has increased tremendously over the past 15 years. Progress has come in "broad strokes", and a number of important details and complex questions remain to be addressed. It is anticipated that this is a "work in progress", and that the precise models for the neural regulation of PPI will evolve substantially in the coming years.