Paraventricular hypothalamic and amygdalar CRF neurons synapse in the external globus pallidus

Abstract

Stress evokes directed movement to escape or hide from potential danger. Corticotropin-releasing factor (CRF) neurons are highly activated by stress; however, it remains unclear how this activity participates in stress-evoked movement. The external globus pallidus (GPe) expresses high levels of the primary receptor for CRF, CRFR1, suggesting the GPe may serve as an entry point for stress-relevant information to reach basal ganglia circuits, which ultimately gate motor output. Indeed, projections from CRF neurons are present within the GPe, making direct contact with CRFR1-positive neurons. CRFR1 expression is heterogenous in the GPe; prototypic GPe neurons selectively express CRFR1, while arkypallidal neurons do not. Moreover, CRFR1-positive GPe neurons are excited by CRF via activation of CRFR1, while nearby CRFR1-negative neurons do not respond to CRF. Using monosynaptic rabies viral tracing techniques, we show that CRF neurons in the stress-activated paraventricular nucleus of the hypothalamus (PVN), central nucleus of the amygdala (CeA), and bed nucleus of the stria terminalis (BST) make synaptic connections with CRFR1-positive neurons in the GPe an unprecedented circuit connecting the limbic system with the basal ganglia. CRF neurons also make synapses on Npas1 neurons, although the majority of Npas1 neurons are arkypallidal and do not express CRFR1. Interestingly, prototypic and arkypallidal neurons receive different patterns of innervation from CRF-rich nuclei. Hypothalamic CRF neurons preferentially target prototypic neurons, while amygdalar CRF neurons preferentially target arkypallidal neurons, suggesting that these two inputs to the GPe may have different impacts on GPe output. Together, these data describe a novel neural circuit by which stress-relevant information carried by the limbic system signals in the GPe via CRF to influence motor output.

Npas1+-Nkx2.1+Neurons Are an Integral Part of the Cortico-pallido-cortical Loop

“…They are commonly referred to as prototypic neurons. We (this study) and others noted that prototypic neurons are not simply a single class of neurons (Abdi et al, 2015;Abrahao and Lovinger, 2018;Dodson et al, 2015;Flandin et al, 2010;Hunt et al, 2018;Mastro et al, 2014;Nobrega-Pereira et al, 2010;Oh et al, 2017;Saunders et al, 2018;Saunders et al, 2015). Instead, this group encompasses a heterogeneous population of neurons, and their properties remain to be fully described.…”

“…Though cortical input is known to reach the GPe through the cortico-dStr-GPe and the cortico-STN-GPe pathways (Jaeger and Kita, 2011), there is increasing evidence of direct cortical input to the GPe (Milardi et al, 50 2015;Naito & Kita, 1994;Smith & Wichmann, 2015). Using rabies virus tracing, we have recently confirmed the existence of cortical input to GPe neurons (Hunt et al, 2018). However, with the low density mapping and manual quantification, we were not able to provide a more complete representation of the input regions and their relative size.…”

Individual variability in behavior and functional networks predicts vulnerability using a predator scent model of PTSD

“…ZI-pituitary gland and ZI-visceral cortex) may be involved in control of sympathetic visceral reactions and the hypothalamus–pituitary–adrenal (HPA) axis activity 30 . Lastly, the GP-PVN hypothalamus projection, known to involve corticotropin-releasing factor (CRF) neurons, were reported to link stress response to motor output 31 .…”

“…Another interesting circuit that is coupled to freezing behavior is the PVN-GP connection. CRF neurons in the PVN hypothalamus, amygdala and BNST send synapses to the external GP 31 , which expresses high levels of the primary CRF receptor (i.e. CRFR1).…”

“…CRFR1). These connections makes GP an entry point connecting the stress system with the basal ganglia, which links the stress-relevant information to the directed movement 31 . Consistent with this notion, our data suggest that the pre-trauma connectivity in this circuit is directly associated with stress-related behaviors in animals.…”