Neural substrates underlying fear‐evoked freezing: the periaqueductal grey–cerebellar link

Abstract

The central neural pathways involved in fear-evoked behaviour are highly conserved across mammalian species, and there is a consensus that understanding them is a fundamental step towards developing effective treatments for emotional disorders in man. The ventrolateral periaqueductal grey (vlPAG) has a well-established role in fear-evoked freezing behaviour. The neural pathways underlying autonomic and sensory consequences of vlPAG activation in fearful situations are well understood, but much less is known about the pathways that link vlPAG activity to distinct fear-evoked motor patterns essential for survival. In adult rats, we have identified a pathway linking the vlPAG to cerebellar cortex, which terminates as climbing fibres in lateral vermal lobule VIII (pyramis). Lesion of pyramis input–output pathways disrupted innate and fear-conditioned freezing behaviour. The disruption in freezing behaviour was strongly correlated to the reduction in the vlPAG-induced facilitation of α-motoneurone excitability observed after lesions of the pyramis. The increased excitability of α-motoneurones during vlPAG activation may therefore drive the increase in muscle tone that underlies expression of freezing behaviour. By identifying the cerebellar pyramis as a critical component of the neural network subserving emotionally related freezing behaviour, the present study identifies novel neural pathways that link the PAG to fear-evoked motor responses.

Neural Correlates of Fear in the Periaqueductal Gray

“…1 C ). Consistent with previous studies (Duvarci et al, 2011; Koutsikou et al, 2014), exposure to a CS tone previously associated with an aversive foot shock produced a statistically significant increase in freezing during EE (CS blocks 1–3; ANOVA with Tukey's post hoc test between baseline and CS blocks 1, 2, or 3, p < 0.0001, F (8,90) = 40.6, n = 17) compared with preconditioning baseline. For example, during CS block 1, animals spent 82.8 ± 4% of their time freezing compared with 27.1 ± 3% of their time during baseline trials (Fig.…”

“…At the end of the CS-only session, rats were returned to their home cages. After 24 h (experimental day 4), a piece of filter paper impregnated with cat odor was placed in the top of their home cages to test innate fear responses (exposure duration ∼3 min; Koutsikou et al, 2014). …”

“…The networks that coordinate innate behaviors include dorsal regions of the PAG (dorsal PAG, dPAG; including dorsal, dorsolateral, and lateral columns; Bandler and Depaulis, 1988; Fanselow et al, 1991; Walker and Davis, 1997; De Oca et al, 1998; Vianna et al, 2001a), whereas those that orchestrate learned behaviors include the ventral PAG (vPAG; notably its ventrolateral column; Bandler and Shipley, 1994; Bandler et al, 2000; Vianna et al, 2001b; Helmstetter et al, 2008). Depending on context (e.g., proximity of threat), both innate and learned defense behaviors include freezing (Bowen et al, 2013; Koutsikou et al, 2014). …”

The neural circuits of innate fear: detection, integration, action, and memorization

“…The PAGvl seems to mediate these passive defensive responses though its downstream projections to the ventromedial and ventrolateral medulla and to the cerebellum (Vianna and Brandão 2003;Koutsikou et al 2014;Tovote et al 2016). However, here too, the precise contribution of each target structure to the different behavioral outcomes remains to be determined.…”

The Role of the Cerebellum in Unconscious and Conscious Processing of Emotions: A Review

“…Furthermore, the vermis is connected with limbic areas-such as the amygdala, hippocampus [90], periaqueductal gray [94,95], and sensory cortices [96,97]-which function in emotional learning during fear conditioning and generate the appropriate emotional behavior patterns [94,95].…”