Feeling Jumpy: Orexins and the Startle Reflex

We all know what happens when we get startled—tensed muscles, a jump, a hard blinking of the eyes. It turns out that this very reaction is the same among many species. In the laboratory, the startle response can be used to objectively measure anxiety and emotional states in humans as well as laboratory animals. People with posttraumatic stress disorder, obsessive-compulsive disorder, anxiety, or panic disorder all show increased startle response reflexes. In humans, this is typically measured by determining the magnitude of the muscle activity of the eyeblink reflex during the emission of a sudden loud noise. In laboratory animals, the magnitude of a whole-body jump in response to a sudden loud noise is measured.

The startle test is often taken a step further in order to assess associative memory and learning capacity in the form of fear-potentiated startle (FPS). In this paradigm, subjects are trained to associate an aversive unconditioned stimulus (such as a mild shock) with a non-aversive conditioned cue stimulus (such as a colored light). When presented with the cue stimulus alone, subjects will show a startle response in the absence of the aversive shock. When presented with the cue stimulus and a loud noise, a normal subject’s startle response will be increased compared with presentation of the loud noise without the conditioned cue stimulus. This increase in startle response is taken as the objective measurement of an evoked state of fear. The heightened startle is also evidence of memory capabilities.

The basics of the startle reflex are well-described, making this a reliable model to assess levels of anxiety and memory skills. However, the brain circuitry involved is complex, and the precise neurobiology of the reflex is still under investigation (Zhao and Davis 2004)

In this week’s issue of the journal Psychopharmacology, Steiner et al. publish their work addressing the role of orexin neuropeptide signaling in the startle reflex. Orexin-producing neurons are located in the hypothalamus, but have connections to the amygdala. The amygdala is required for startle reflex as well as emotional processing. Orexin signaling has been shown to increase alertness and wakefulness, regulate metabolism, as well as play a role in motivation and addiction (Brisbare-Roch et al., 2007; Scammell and Saper, 2007). The orexin system is a promising field that is still in an early phase of research.

Steiner et al. tested fear-potentiated startle in rats receiving the orexin receptor antagonist almorexant. Thus, with blocked orexin receptors, fear-potentiated startle response was decreased, indicating a role for orexins in the induction of fear-potentiated startle. However, this result could also be explained if almorexant simply reduced overall anxiety levels. To test for this possibility, the authors used the elevated plus maze. Basal anxiety levels did not seem to be altered by blocking orexin receptors, as rats treated with almorexant performed similarly in the elevated plus maze to untreated rats. These findings indicate that blocking orexin signaling affects associative learning, thereby decreasing fear-potentiated startle, without changing overall anxiety. With further study, this finding could have implications for the orexin system in learning and memory.

What do you think?

If the almorexant blocks potentiation of the conditioned startle response, does it affect fear memory?

What kind of therapeutic potential could this have?

Further Reading:

Brisbare-Roch C, Dingemanse J, Koberstein R, Hoever P, Aissaoui H, Flores S, Mueller C, Nayler O, van Gerven J, de Haas SL, Hess P, Qiu C, Buchmann S, Scherz M, Weller T, Fischli W, Clozel M, Jenck F. (2007). Promotion of sleep by targeting the orexin system in rats, dogs and humans. Nat Med. Feb;13(2):150-5.

Scammell TE and Saper CB. (2007). Orexins: looking forward to sleep, back at addiction Nature Medicine 13, 126 – 128.

Steiner MA, Lecourt H, Jenck F. (2012). The brain orexin system and almorexant in fear-conditioned startle reactions in the rat. Psychopharmacology (Berl). May 17.

Zhao Z, and Davis M. (2004). Fear-Potentiated Startle in Rats Is Mediated by Neurons in the Deep Layers of the Superior Colliculus/Deep Mesencephalic Nucleus of the Rostral Midbrain through the Glutamate Non-NMDA Receptors. J Neurosci, November 17, 24(46):10326 –10334.