Abstract
A large majority of neurons in the superficial layer of the dorsal horn projects to the lateral parabrachial nucleus (LPB). LPB neurons then project to the capsular part of the central amygdala (CeA; CeC), a key structure underlying the nociception-emotion link. LPB-CeC synaptic transmission is enhanced in various pain models by using electrical stimulation of putative fibers of LPB origin in brain slices. However, this approach has limitations for examining direct monosynaptic connections devoid of directly stimulating fibers from other structures and local GABAergic neurons. To overcome these limitations, we infected the LPB of rats with an adeno-associated virus vector expressing channelrhodopsin-2 and prepared coronal and horizontal brain slices containing the amygdala. We found that blue light stimulation resulted in monosynaptic excitatory postsynaptic currents (EPSCs), with very small latency fluctuations, followed by a large polysynaptic inhibitory postsynaptic current in CeC neurons, regardless of the firing pattern type. Intraplantar formalin injection at 24 h before slice preparation significantly increased EPSC amplitude in late firing-type CeC neurons. These results indicate that direct monosynaptic glutamatergic inputs from the LPB not only excite CeC neurons but also regulate CeA network signaling through robust feed-forward inhibition, which is under plastic modulation in response to persistent inflammatory pain.
Highlights
NOCICEPTION SIGNALS CONVERGING on the spinal dorsal horn or spinal trigeminal nucleus from the periphery are first integrated in these structures and conveyed to the brain loci underlying the central processing of nociceptive information, thereby triggering acute nociception-associated responses and chronic changes associated with pain, such as chronic painrelated emotional complications (Hashmi et al 2013)
With the use of projection-specific optogenetic activation of the lateral parabrachial nucleus (LPB)-CeC pathway, we have found the following: 1) the LPB sends direct excitatory projections that form monosynaptic glutamatergic synapses with CeC neurons; 2) such direct inputs could be recorded from a large majority of CeC neurons regardless of their firing pattern; 3) excitatory postsynaptic responses in CeC neurons induced by light-evoked excitation of these fibers are followed by a large component of GABA receptor-mediated postsynaptic components; 4) light-evoked excitation of these pathway results in inhibitory-predominant integrated and sustained responses in CeM neurons; and 5) LPB-CeC synaptic transmission activated by optogenetic excitation shows robust potentiation in a persistent inflammatory pain model
In many previous studies using slice preparations, postsynaptic responses in CeC neurons were evoked by electrical stimulation of their afferent fibers with electrodes placed on putative regions medio-dorsal to the CeM, with the assumption that the fibers arising from the LPB were stimulated (Ikeda et al 2007; Neugebauer et al 2003; Watabe et al 2013)
Summary
NOCICEPTION SIGNALS CONVERGING on the spinal dorsal horn or spinal trigeminal nucleus from the periphery are first integrated in these structures and conveyed to the brain loci underlying the central processing of nociceptive information, thereby triggering acute nociception-associated responses and chronic changes associated with pain, such as chronic painrelated emotional complications (Hashmi et al 2013). A large portion of these ascending fibers projecting to various structures has axon collaterals projecting to the LPB, suggesting that a “carbon copy” of most of the nociceptive information sent from the spinal cord to a specific brain site is sent to the LPB (Todd 2010) The importance of this spino (trigemino)-parabrachial projection in terms of pain signaling is strengthened further by accumulating lines of evidence indicating that neurons in the LPB project to the capsular part of the central amygdala (CeA; CeC) and convey the nociceptive signals (Dong et al 2010; Gauriau and Bernard 2002; Hunt and Mantyh 2001; Jasmin et al 1997; Sarhan et al 2005; Todd 2010). Two reports demonstrated an involvement of the LPB-CeC pathway in fear/threat acquisition, independently using gene expressionand projection-specific optogenetic activation of this pathway (Han et al 2015; Sato et al 2015)
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