The Periaqueductal Gray Orchestrates Sensory and Motor Circuits at Multiple Levels of the Neuraxis

Abstract

The periaqueductal gray (PAG) coordinates behaviors essential to survival, including striking changes in movement and posture (e.g., escape behaviors in response to noxious stimuli vs freezing in response to fear-evoking stimuli). However, the neural circuits underlying the expression of these behaviors remain poorly understood. We demonstrate in vivo in rats that activation of the ventrolateral PAG (vlPAG) affects motor systems at multiple levels of the neuraxis through the following: (1) differential control of spinal neurons that forward sensory information to the cerebellum via spino-olivo-cerebellar pathways (nociceptive signals are reduced while proprioceptive signals are enhanced); (2) alterations in cerebellar nuclear output as revealed by changes in expression of Fos-like immunoreactivity; and (3) regulation of spinal reflex circuits, as shown by an increase in ␣-motoneuron excitability. The capacity to coordinate sensory and motor functions is demonstrated in awake, behaving rats, in which natural activation of the vlPAG in fear-conditioned animals reduced transmission in spino-olivo-cerebellar pathways during periods of freezing that were associated with increased muscle tone and thus motor outflow. The increase in spinal motor reflex excitability and reduction in transmission of ascending sensory signals via spinoolivo-cerebellar pathways occurred simultaneously. We suggest that the interactions revealed in the present study between the vlPAG and sensorimotor circuits could form the neural substrate for survival behaviors associated with vlPAG activation.

Neural activity in the periaqueductal gray and other specific subcortical structures is enhanced when a selective serotonin reuptake inhibitor selectively prevents seizure‐induced sudden death in the DBA/1 mouse model of sudden unexpected death in epilepsy

“…Thus, in the subcortical auditory network, the activity of the only previously identified ROI (SOC) was unchanged in the Flx+Sz group as compared to the Sal+Sz+RA group, suggesting that fluoxetine's effects on this structure are not critical for S-IRA block. 5,[22][23][24][39][40][41] The significant decrease in PAG activity seen in the DBA/1 mice that exhibited S-IRA (Sal+Sz+RA) when compared to the mice not subjected to seizure (Sal-noSz) strongly suggests that activation of the PAG did not occur in response to the apnea that resulted in S-IRA. 37 In the SML network, the amygdala, PAG, and RF ROIs showed significant increases in activity.…”

“…These mice also show spontaneous absencelike seizures accompanied by spike-wave discharges on the electroenceophalogram. [22][23][24] Evidence for the involvement of specific brainstem structures, including the PAG, as regions of interest (ROIs) in seizure-induced death in DBA/1 mice has also been observed in a manganese-enhanced magnetic resonance neuroimaging (MEMRI) study. 8,10,15,16 Neuroimaging studies have observed pathological changes in brainstem structures, including the periaqueductal gray (PAG), in patients who subsequently exhibited SUDEP.…”

“…[19][20][21] The PAG plays a particularly important compensatory role for respiratory distress that occurs in numerous exigent situations. [22][23][24] Evidence for the involvement of specific brainstem structures, including the PAG, as regions of interest (ROIs) in seizure-induced death in DBA/1 mice has also been observed in a manganese-enhanced magnetic resonance neuroimaging (MEMRI) study. 25 These results suggest that the seizure network interacts with specific brainstem structures, leading to impaired respiratory and arousal functions in this model of seizure-induced death.…”

Functional movement disorders

“…Lack of habituation in amygdalar activity over time suggests a general hyperarousal state in FND. Patients may be more prone than healthy controls to automatic motor defense behavior, such as freeze response, mediated by PAG abnormal activity, because this region is known to be implicated in the freeze response in both animal [65] and human [66,67…”

Cerebellar physiology: links between microcircuitry properties and sensorimotor functions

“…In this process, however, the synapses that were initially given a low weight may at a later stage of more mature synaptic weight distributions gradually become useful to the system again. Therefore, it is necessary that the parallel fibre synapses on Koutsikou et al (2015). Cerebellar cortical zones are indicated as in Fig.…”