Age-related neuroinflammation and pathology in the locus coeruleus and hippocampus: beta-adrenergic antagonists exacerbate impairment of learning and memory in aged mice
| Autor: | Gaku Ogawa, Mehrdad Shamloo, Ryan D. Leib, Nay Lui Saw, Andrew K. Evans, Kratika Singhal, Heui Hye Park |
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| Rok vydání: | 2021 |
| Předmět: |
Male
0301 basic medicine Aging Pathology medicine.medical_specialty Adrenergic beta-Antagonists Hippocampus Hippocampal formation Receptors N-Methyl-D-Aspartate Article 03 medical and health sciences 0302 clinical medicine Memory Animals Learning Medicine Clenbuterol Cognitive Dysfunction Fear conditioning Cognitive decline Neuroinflammation Beta-adrenergic blocking agent business.industry General Neuroscience Adrenergic beta-Agonists Propranolol Mice Inbred C57BL 030104 developmental biology nervous system Neuroinflammatory Diseases NMDA receptor Locus coeruleus Locus Coeruleus Neurology (clinical) Inflammation Mediators Geriatrics and Gerontology business 030217 neurology & neurosurgery Developmental Biology |
| Zdroj: | Neurobiol Aging |
| ISSN: | 0197-4580 |
| Popis: | The locus coeruleus (LC) provides the primary noradrenergic input to the forebrain and hippocampus, and may be vulnerable to degeneration and contribute to age-related cognitive decline and neuroinflammation. Additionally, inhibition of noradrenergic transmission by brain-permeable beta-blockers could exacerbate cognitive impairment. This study examined effects of age and acute beta-blocker administration on LC and hippocampus pathology, neuroinflammation and learning and memory behavior in mice. Male mice, 3 and 18 months old, were administered propranolol (beta-blocker) or mabuterol (beta-adrenergic agonist) acutely around behavioral assessment. Terminal inflammatory markers in plasma, hippocampus and LC were assessed alongside histopathology. An increase in hippocampal and LC microgliosis and inflammatory proteins in the hippocampus was detected in aged mice. We report pathological hyperphosphorylation of the postsynaptic NMDA receptor subunit 2B (NR2B) in the hippocampus, suggesting neuronal hyperexcitability. Furthermore, the aged proteome revealed an induction in proteins related to energy metabolism, and mitochondria dysfunction in the LC and hippocampus. In a series of hippocampal dependent behavioral assessment tasks acute beta-adrenergic agonist or beta blocker administration altered learning and memory behavior in both aged and young mice. In Y-maze, propranolol and mabuterol differentially altered time spent in novel versus familiar arms in young and aged mice. Propranolol impaired Novel Object Recognition in both young and aged mice. Mabuterol enhanced trace learning in fear conditioning. Aged mice froze more to context and less to cue. Propranolol impaired contextual recall in aged mice. Concluding, aged mice show LC and hippocampus pathology and heightened effects of beta-adrenergic pharmacology on learning and memory. |
| Databáze: | OpenAIRE |
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