How the forebrain transitions to adulthood: developmental plasticity markers in a long-lived rodent reveal region diversity and the uniqueness of adolescence.

Maturation of the forebrain involves transitions from higher to lower levels of synaptic plasticity. The timecourse of these changes likely differs between regions, with the stabilization of some networks scaffolding the development of others. To gain better insight into neuroplasticity changes associated with maturation to adulthood, we examined the distribution of two molecular markers for developmental plasticity. We conducted the examination on male and female degus (Octodon degus), a rodent species with a relatively long developmental timecourse that offers a promising model for studying both development and age-related neuropathology. Immunofluorescent staining was used to measure perineuronal nets (PNNs), an extracellular matrix structure that emerges during the closure of critical plasticity periods, as well as microglia, resident immune cells that play a crucial role in synapse remodeling during development. PNNs (putatively restricting plasticity) were found to be higher in non-juvenile (>3 month) degus, while levels of microglia (putatively mediating plasticity) decreased across ages more gradually, and with varying timecourses between regions. Degus also showed notable variation in PNN levels between cortical layers and hippocampal subdivisions that have not been previously reported in other species. These results offer a glimpse into neuroplasticity changes occurring during degu maturation and highlight adolescence as a unique phase of neuroplasticity, in which PNNs have been established but microglia remain relatively high.

First International Conference on Unconventional Animal Models of Alzheimer's Disease and Aging.

The first International Conference on Unconventional Animal Models of Alzheimer's Disease and Aging (UAMAA) took place on December 13-16, 2023, in Santiago, Chile. The Alzheimer's disease (AD) research field is currently in search for new and unconventional models that could hold greater translational potential than transgenic mouse models. Thus this UAMAA conference is timely and significant. The event consisted of 6 sessions with talks from 28 world-class scientists from all over the world. These animal models of interest include the degu (Octodon degu), the dog (Canis familiaris), and certain species of nonhuman primates that may better recapitulate neuropathology and cognitive impairments in human AD. Our conference has provided a formal forum to discuss and highlight new research directions, alternative animal models, and innovative approaches for the AD and aging research field.

Anatomical and molecular characterization of parvalbumin-cholecystokinin co-expressing inhibitory interneurons: implications for neuropsychiatric conditions.

Inhibitory interneurons are crucial to brain function and their dysfunction is implicated in neuropsychiatric conditions. Emerging evidence indicates that cholecystokinin (CCK)-expressing interneurons (CCK+) are highly heterogenous. We find that a large subset of parvalbumin-expressing (PV+) interneurons express CCK strongly; between 40 and 56% of PV+ interneurons in mouse hippocampal CA1 express CCK. Primate interneurons also exhibit substantial PV/CCK co-expression. Mouse PV+/CCK+ and PV+/CCK- cells show distinguishable electrophysiological and molecular characteristics. Analysis of single nuclei RNA-seq and ATAC-seq data shows that PV+/CCK+ cells are a subset of PV+ cells, not of synuclein gamma positive (SNCG+) cells, and that they strongly express oxidative phosphorylation (OXPHOS) genes. We find that mitochondrial complex I and IV-associated OXPHOS gene expression is strongly correlated with CCK expression in PV+ interneurons at both the transcriptomic and protein levels. Both PV+ interneurons and dysregulation of OXPHOS processes are implicated in neuropsychiatric conditions, including autism spectrum (ASD) disorder and schizophrenia (SCZ). Analysis of human brain samples from patients with these conditions shows alterations in OXPHOS gene expression. Together these data reveal important molecular characteristics of PV-CCK co-expressing interneurons and support their implication in neuropsychiatric conditions.

Cognitively impaired aged Octodon degus recapitulate major neuropathological features of sporadic Alzheimer's disease.

The long-lived Chilean rodent (Octodon degus) has been reported to show spontaneous age-dependent neuropathology and cognitive impairments similar to those observed in human AD. However, the handful of published papers on degus of differing genetic backgrounds yield inconsistent findings about sporadic AD-like pathological features, with notably differing results between lab in-bred degus versus outbred degus. This motivates more extensive characterization of spontaneously occurring AD-like pathology and behavior in degus. In the present study, we show AD-like neuropathological markers in the form of amyloid deposits and tau abnormalities in a cognitively impaired subset of aged outbred degus. Compared to the aged degus that show normal burrowing behavior, the age-matched degus with burrowing behavior deficits correlatively exhibit detectable human AD-like Aß deposits and tau neuropathology, along with neuroinflammatory markers that include enhanced microglial activation and higher numbers of reactive astrocytes in the brain. This subset of cognitively impaired aged degus also exhibits cerebral amyloid angiopathy and tauopathy. We find robust neurodegenerative features in behaviorally deficient aged degus, including hippocampal neuronal loss, altered parvalbumin and perineuronal net staining in the cortex, and increased c-Fos neuronal activation in the cortex that is consistent with the neural circuit hyperactivity reported in human AD patients. By focusing on the subset of aged degus that show AD-like behavioral deficits and correlative neuropathology, our findings establish outbred degus as a natural model of sporadic AD and demonstrate the potential importance of wild-type outbred genetic backgrounds for AD pathogenesis.

Genome Sequencing Variations in the Octodon degus, an Unconventional Natural Model of Aging and Alzheimer's Disease.

The degu (Octodon degus) is a diurnal long-lived rodent that can spontaneously develop molecular and behavioral changes that mirror those seen in human aging. With age some degu, but not all individuals, develop cognitive decline and brain pathology like that observed in Alzheimer's disease including neuroinflammation, hyperphosphorylated tau and amyloid plaques, together with other co-morbidities associated with aging such as macular degeneration, cataracts, alterations in circadian rhythm, diabetes and atherosclerosis. Here we report the whole-genome sequencing and analysis of the degu genome, which revealed unique features and molecular adaptations consistent with aging and Alzheimer's disease. We identified single nucleotide polymorphisms in genes associated with Alzheimer's disease including a novel apolipoprotein E (Apoe) gene variant that correlated with an increase in amyloid plaques in brain and modified the in silico predicted degu APOE protein structure and functionality. The reported genome of an unconventional long-lived animal model of aging and Alzheimer's disease offers the opportunity for understanding molecular pathways involved in aging and should help advance biomedical research into treatments for Alzheimer's disease.