Neogenin in Amygdala for Neuronal Activity and Information Processing

Abstract

Fear learning and memory are vital for livings to survive, dysfunctions in which have been implicated in various neuropsychiatric disorders. Appropriate neuronal activation in amygdala is critical for fear memory. However, the underlying regulatory mechanisms are not well understood. Here we report that Neogenin, a DCC (deleted in colorectal cancer) family receptor, which plays important roles in axon navigation and adult neurogenesis, is enriched in excitatory neurons in BLA (Basolateral amygdala). Fear memory is impaired in male mutant mice. The number of cFos neurons in response to tone-cued fear training was reduced in mutant mice, indicating aberrant neuronal activation in the absence of Neogenin. Electrophysiological studies show that mutation reduced the cortical afferent input to BLA pyramidal neurons and compromised both induction and maintenance of Long-Term Potentiation evoked by stimulating cortical afferent, suggesting a role of Neogenin in synaptic plasticity. Concomitantly, there was a reduction in spine density and in frequency of miniature excitatory postsynaptic currents (mEPSCs), but not miniature inhibitory postsynaptic currents, suggesting a role of Neogenin in forming excitatory synapses. Finally, ablating in the BLA in adult male mice impaired fear memory likely by reducing mEPSC frequency in BLA excitatory neurons. These results reveal an unrecognized function of Neogenin in amygdala for information processing by promoting and maintaining neurotransmission and synaptic plasticity and provide insight into molecular mechanisms of neuronal activation in amygdala. Appropriate neuronal activation in amygdala is critical for information processing. However, the underlying regulatory mechanisms are not well understood. Neogenin is known to regulate axon navigation and adult neurogenesis. Here we show that it is critical for neurotransmission and synaptic plasticity in the amygdala and thus fear memory by using a combination of genetic, electrophysiological, behavioral techniques. Our studies identify a novel function of Neogenin and provide insight into molecular mechanisms of neuronal activation in amygdala for fear processing.

Traumatic Stress Produces Delayed Alterations of Synaptic Plasticity in Basolateral Amygdala

“…Considering the significant increase in the number of dendritic spines in BLA in SPS(10d) group, the observed enhancement of mEPSCs frequency in our study may be induced, at least in part, by the increase in the number of functional excitatory synapses. Under some circumstances, some other studies have reported that an increase in the number of dendrites spines accompanies an enhancement of frequency of mEPSCs (Wissman et al, 2011; Montalbano et al, 2013; Bochner et al, 2014; Yasmin et al, 2016; Schilling et al, 2017; Sun et al, 2018). However, the increased number of spines, especially large spines, would be predictive of an increase in the expression of postsynaptic excitatory receptors and subsequently larger mEPSCs amplitude (Lee et al, 2015; Udagawa et al, 2015; Awad et al, 2016; Deng et al, 2019).…”

Axon guidance modalities in CNS regeneration revealed by quantitative proteomic analysis

“…Among them, several guidance factors were detected such as Robo2, EphB3, RGMA (Repulsive guidance molecule A), and Slik5 (Slit and NTRK-like family member 5). Although originally described as regulators of axon navigation in the developing nervous system, these guidance factors persist throughout adult life and are implicated in physiological processes such as synapse maintenance and strengthening (Sun et al, 2018), in particular at the closure of the critical plastic period of development (Fawcett, 2009). On the other hand, in the context of regeneration, the presence of repulsive cues may impair the growth capacity of regenerating axons and/or misguide them away from their proper targets.…”

Rap1b but not Rap1a in the forebrain is required for learned fear

“…By contrast, a negative correlation exists between ventral mPFC neural activity and heart rate [ 29 ]. In rodents, large amounts of evidence indicate a higher level of fear expression coincides with increased PL and/or BLA neural activity [ 30 , 31 ], and augmented IL activity is linked to constrained fear [ 32 – 34 ]. As such, abnormal neural activity in the above mentioned three brain areas can readily cause irregular fear expression.…”