Neuronal Network Interactions in the Startle Reflex, Learning Mechanisms, and CNS Disorders, Including Sudden Unexpected Death in Epilepsy

Abstract As discussed in this book, there are many primary neuronal networks that mediate important physiological functions of the central nervous system (CNS), including vision, hearing, locomotion, and respiration. Each of these normal networks can interact with other primary networks to mediate important cross-network functions, and the interaction can be either additive or competitive. An example of an additive or positive form of network interaction is seen in sensorimotor integration, including the visual-motor interactions that mediate eye movements in response to visual stimuli. Primary networks can also interact with nonprimary conditional multireceptive networks, leading to the emergence of more complex phenomena. These phenomena include certain forms of learning as well as CNS disorders, including, for example, those that can lead to death in epilepsy. Neuronal networks can compete with each other to reduce the network function. This occurs, for example, when an acoustic stimulus can induce cessation of locomotion in a learning paradigm such as fear conditioning. A negative interaction is also seen in the prototypical competitive network interaction that forms the basis of the original and conceptually important network interaction hypothesis, the gate control theory of pain. This network competition mechanism is proposed to be a critical mechanism mediating the therapeutic stimulation paradigms currently used to treat many CNS disorders. Network interactions are mediated by (1) direct electrophysiological connections between network neurons that release endogenous neuroactive substances via synaptic transmission and (2) indirect interactions that release these substances via volume transmission. These network interactions can occur essentially instantaneously or sequentially over a finite time course. The interactions can involve two networks, as in the somatosensory-motor network interactions, which occur in the tactile startle response, and are also seen in the interaction of the pain network with the therapeutic network initiated by certain pain-relieving electrical stimulation therapies. The network interactions can be more complex, involving three or more networks, and examples of multinetwork interaction include fear-potentiated startle, seizure-induced analgesia, and audiogenic seizure kindling. An example of such a multinetwork interaction with fatal consequences is proposed to occur in the CNS disorder of epilepsy called sudden unexpected death in epilepsy (SUDEP). The DBA/1 and DBA/2 mouse models of SUDEP involve additive interactions between the auditory and locomotor networks and a subsequent negative interaction with the respiratory network, which results in respiratory arrest. These network interactions may be mediated, in part, by the release of endogenous neuroactive substances that inhibit (e.g. adenosine) or enhance (e.g. serotonin) the activity of the respiratory network via synaptic and/or volume transmission. Thus, investigations of network interactions in normal situations and in CNS disorders may provide the keys to understanding learning mechanisms and also for treating CNS disorders with stimulation and/or pharmacological paradigms.