Mapping Cell Types and Efferent Pathways in the Ascending Relaxin-3 System of the Nucleus Incertus

Abstract

Please list the following information on your separate title page in Word .DOC format in the order listed below and upload as a Title Page file at submission 1. Manuscript Title (50 word maximum) Mapping cell types and efferent pathways in the ascending relaxin-3 system of the nucleus incertus 2. Abbreviated Title (50 character maximum) Mapping the relaxin-3 system of the nucleus incertus 3. List all Author Names and Affiliations in order as they would appear in the published article

Involvement of the Nucleus Incertus and Relaxin-3/RXFP3 Signaling System in Explicit and Implicit Memory

“…This column is ventrolaterally located to the aqueduct, but in 20–40 μm coronal sections, only 3–4 relaxin-3 positive neurons appear in each hemisphere, but the total number of relaxin-3 neurons represents 50% of the number in the NI. Thus, these neurons should be considered as a relevant source of relaxin-3 in the brain (Blasiak et al, 2013 ), particularly as part of the brainstem intrinsic circuitry (Nasirova et al, 2020 ). Furthermore, anatomical data suggest that the pontine raphe nucleus is a rostral extension of the NI (Nasirova et al, 2020 ).…”

“…Thus, these neurons should be considered as a relevant source of relaxin-3 in the brain (Blasiak et al, 2013 ), particularly as part of the brainstem intrinsic circuitry (Nasirova et al, 2020 ). Furthermore, anatomical data suggest that the pontine raphe nucleus is a rostral extension of the NI (Nasirova et al, 2020 ). While it is often considered a serotoninergic nucleus (Hale and Lowry, 2011 ), the number of neurons positive for serotonin (5-HT) in the pontine raphe nucleus is lower than the number of relaxin-3 positive neurons (Tanaka et al, 2005 ).…”

“…NI has widespread connections to telencephalic centers that play a major role in the acquisition, storage, and retrieval of explicit (hippocampal-dependent) and implicit (amygdala-dependent) memories. NI connections include subcortical centers that modulate hippocampal and amygdala function, including the MS, supramammillary nuclei, and both the median and dorsal raphe nuclei in the rat (Goto et al, 2001 ; Olucha-Bordonau et al, 2003 ), mouse (Smith et al, 2010 ; Szönyi et al, 2019 ; Lu et al, 2020 ; Nasirova et al, 2020 ) and non-human primate (Ma et al, 2009b ).…”

“…The opposing effects of the NI stimulation on theta might be explained by the assessment of different neuronal targets. However, most neurons of the NI express glutamic acid dehydrogenase (GAD) in the rat (Olucha-Bordonau et al, 2003 ; Ma et al, 2007 ) and mouse (Szönyi et al, 2019 ), and a recent report confirms that all NMB neurons are vGAT-positive (i.e., GABAergic; Nasirova et al, 2020 ). However, the surrounding nuclei contain GABA neurons (Nasirova et al, 2020 ) that when stimulated, as occurs in the vGAT-Cre mouse (Szönyi et al, 2019 ) could produce complex interactions leading to different behaviors to those obtained from specific activation of NMB neurons (Lu et al, 2020 ).…”

“…At the same time, it was discovered that the rat NI contained neurons producing the neuropeptide, relaxin-3 (Burazin et al, 2002 ; Tanaka et al, 2005 ; Ma et al, 2007 ), which interacted with multiple stress and arousal transmitter systems (Ma et al, 2013 , 2017b ; Blasiak et al, 2015 ). Thus, the NI is a complex structure composed predominantly of GABAergic neurons in the rat (Ford et al, 1995 ; Olucha-Bordonau et al, 2003 ; Ma et al, 2007 ) and mouse (Smith et al, 2010 ) brain, and populations of NI GABAergic neurons co-express neuromedin-B (NMB; Lu et al, 2020 ; Nasirova et al, 2020 ), cholecystokinin (Kubota et al, 1983 ; Olucha-Bordonau et al, 2003 ) and/or neurotensin (Jennes et al, 1982 ), as well as relaxin-3, in both species. This neurochemical heterogeneity is also reflected physiologically, as a majority of relaxin-3 neurons in the rat NI increase their firing rate in response to CRF, while non-relaxin-3 neurons can increase or decrease their firing rate (Ma et al, 2013 ).…”