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Anatomical correlates of age‐related basal forebrain dysfunction
Author(s) -
Somera Brandy Lynn,
Woodruff Jennifer L.,
Grillo Claudia A.,
Reagan Lawrence P.,
Fadel James R.
Publication year - 2020
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1002/alz.039896
Subject(s) - neuroscience , basal forebrain , substantia innominata , forebrain , biology , homeostasis , psychology , endocrinology , central nervous system
Background The basal forebrain (BF) is comprised of several nuclei including the substantia innominata, medial septum, nucleus basalis and diagonal band of broca, which are involved in cognitive functions including attention, motivation, and arousal. BF neurons are particularly vulnerable to dysfunction and degeneration in aged humans and, more dramatically, in diseases such as Alzheimer's disease (AD). Age‐related BF dysfunction may reflect diminished afferent regulation, as well as an altered local glial environment. We have previously shown reduced orexin/hypocretin innervation of BF in aging, a phenomenon that may link afferent dysfunction with altered microglial homeostasis. There is little research examining these relationships involving afferent neuronal and glial cell populations in the BF as it relates to aging. The purpose of this study is to compare specific neuronal and glial populations to identify anatomical factors susceptible to age‐related homeostatic dysfunction in the BF. Methods Several lines of evidence demonstrate the responsiveness of the BF to homeostatic stimuli including food related stimuli. Using a food‐paired stimulus to examine effects of aging on physiologically‐relevant afferent stimulation, we deposited the retrograde neuronal tracer cholera toxin B (CTb) in BF of aged (26‐28 months) and young (2‐3 months) F344/Brown Norway F1 hybrid rats and trained them for 7 days. We then combined neural tract‐tracing with functional and phenotypic markers of activation to elucidate neural circuits that may underlie age‐related loss of activation of BF neurons using immunohistochemistry. Additionally, to show that loss of orexin afferents affects inflammation in the BF via microglial dysregulation, we administered a miRNA‐expressing lentivirus designed to knock down Orexin Receptor 2(OXR2) expression in the BF in young and aged rats. We then analyzed phenotypic changes in microglia using immunohistochemistry and ELISA against a panel of inflammatory cytokines. Results Aged rats showed altered activation of BF afferents located in the medial prelimbic cortex, infralimbic cortex, nucleus accumbens, and ventral tegmental area. Furthermore, changes in morphological and cytokine correlates of microglial activation following OXR2 loss can be seen in aged rats. Conclusion Together, these studies compare specific neuronal and glial populations of young and aged rats to identify anatomical factors susceptible to age‐related dysfunction.