Ultrasonic vocal communication of negative affective states in laboratory mice.

The present study focused on locus coeruleus (LC) pathology in aging humans. The LC is a nucleus located within the pontine tegmentum. Although the LC measures only <15 mm in rostro-caudal extent and <3 mm in other dimensions, its neurons generate widespread axonal norepinephrinergic input for the brain and spinal cord. This small brainstem nucleus plays key roles in arousal, attention, memory, sleep-wake regulation, and other functions. Pathology in the LC has been implicated in neuropsychiatric disorders including depression. The LC also is vulnerable to cell loss and proteinopathy during the course of neurodegenerative diseases. More specifically, LC pathologies have been described in the contexts of Alzheimer disease neuropathologic change (ADNC), dementia with Lewy bodies, Parkinson disease, and frontotemporal lobar degeneration (FTLD). The LC appears to be the first site of phosphorylated tau protein pathology in most aging brains, including those with ADNC and in primary age-related tauopathy (PART). The severity of LC cell loss is associated with the cerebral pTau pathologic burden. In terms of clinical-pathological correlation, LC neurodegeneration has been linked to cognitive impairment, both in vivo (ie, according to clinical imaging), and in autopsy series. In addition to global cognition and memory symptoms, LC degeneration may contribute to the behavioral and psychiatric symptoms of dementia (BPSD). In spite of its widely recognized significance in neurodegenerative diseases, the LC remains understudied in the context of TAR-DNA binding protein of 43 kDa (TDP-43) pathology and limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC). LATE-NC affects approximately one-third of autopsied individuals over the age of 85 years and is associated with a distribution of phosphorylated TDP-43 protein (pTDP-43) pathology that is usually restricted to the medial temporal lobe (MTL). Approximately 15% of those with LATE-NC show pTDP-43 proteinopathy outside the MTL, including in both neocortical and subcortical regions as first demonstrated by Josephs et al. However, the full extent of aging-related pTDP-43 pathology, and particularly the involvement of the LC, is incompletely understood.