Amygdala selectively modulates defensive responses evoked from the superior colliculus in non-human primates.

Brain circuitry underlying defensive behaviors includes forebrain modulatory sites, e.g. the amygdala and hypothalamus, and midbrain effector regions, such as the deep/intermediate layers of the superior colliculus (DLSC). When disinhibited, this network biases behavior towards reflexive defense reactions. While well characterized in rodent models, little is known about this system in the primate brain. Employing focal pharmacological manipulations, we have previously shown that activation of the DLSC triggers reflexive defensive responses, including cowering, escape behaviors and defensive vocalizations. Here, we show that activation of the DLSC also disrupts normal dyadic social interactions between familiar pairs of monkeys. When the basolateral complex of the amygdala (BLA) was inhibited concurrent with DLSC activation, cowering behavior was attenuated, whereas escape behaviors and defensive vocalizations were not. Moreover, inhibition of the BLA, previously shown to produce a profound increase in dyadic social interactions, was unable to normalize the decrease in social behavior resulting from DLSC activation. Together these data provide an understanding of forebrain-midbrain interactions in a species and circuit with translational relevance for the psychiatry of anxiety and post-traumatic stress disorders.

Defense-like behaviors evoked by pharmacological disinhibition of the superior colliculus in the primate.

Stimulation of the intermediate and deep layers of superior colliculus (DLSC) in rodents evokes both orienting/pursuit (approach) and avoidance/flight (defense) responses (Dean et al., 1989). These two classes of response are subserved by distinct output projections associated with lateral (approach) and medial (defense) DLSC (Comoli et al., 2012). In non-human primates, DLSC has been examined only with respect to orienting/approach behaviors, especially eye movements, and defense-like behaviors have not been reported. Here we examined the profile of behavioral responses evoked by activation of DLSC by unilateral intracerebral infusions of the GABA(A) receptor antagonist, bicuculline methiodide (BIC), in nine freely moving macaques. Across animals, the most consistently evoked behavior was cowering (all animals), followed by increased vocalization and escape-like behaviors (seven animals), and attack of objects (three animals). The effects of BIC were dose-dependent within the range 2.5-14 nmol (threshold dose of 4.6 nmol). The behaviors and their latencies to onset did not vary across different infusion sites within DLSC. Cowering and escape-like behaviors resembled the defense-like responses reported after DLSC stimulation in rats, but in the macaques these responses were evoked from both medial and lateral sites within DLSC. Our findings are unexpected in the context of an earlier theoretical perspective (Dean et al., 1989) that emphasized a preferential role of the primate DLSC for approach rather than defensive responses. Our data provide the first evidence for induction of defense-like behaviors by activation of DLSC in monkeys, suggesting that the role of DLSC in responding to threats is conserved across species.

Superior colliculus mediates cervical dystonia evoked by inhibition of the substantia nigra pars reticulata.

Cervical dystonia (CD; spasmodic torticollis) can be evoked by inhibition of substantia nigra pars reticulata (SNpr) in the nonhuman primate (Burbaud et al., 1998; Dybdal et al., 2012). Suppression of GABAergic neurons that project from SNpr results in the disinhibition of the targets to which these neurons project. It therefore should be possible to prevent CD by inhibition of the appropriate nigral target region(s). Here we tested the hypothesis that the deep and intermediate layers of the superior colliculus (DLSC), a key target of nigral projections, are required for the emergence of CD. To test this hypothesis, we pretreated the DLSC of four macaques with the GABA(A) agonist muscimol to determine whether this treatment would prevent CD evoked by muscimol infusions in SNpr. Our data supported this hypothesis: inhibition of DLSC attenuated CD evoked by muscimol in SNpr in all four animals. In two of the four subjects, quadrupedal rotations were evoked by muscimol application into SNpr sites that were distinct from those that induced dystonia. We found that inhibition of DLSC did not significantly alter quadrupedal rotations, suggesting that this response is dissociable from the SNpr-evoked CD. Our results are the first to demonstrate a role of DLSC in mediating the expression of CD. Furthermore, these data reveal a functional relationship between SNpr and DLSC in regulating posture and movement in the nonhuman primate, raising the possibility that the nigrotectal pathway has potential as a target for therapeutic interventions for CD.