ABSTRACT
Change history: In this Article, Extended Data Fig. 8 and Extended Data Table 1 contained errors, which have been corrected online.
ABSTRACT
Changes in gamma oscillations (20-50 Hz) have been observed in several neurological disorders. However, the relationship between gamma oscillations and cellular pathologies is unclear. Here we show reduced, behaviourally driven gamma oscillations before the onset of plaque formation or cognitive decline in a mouse model of Alzheimer's disease. Optogenetically driving fast-spiking parvalbumin-positive (FS-PV)-interneurons at gamma (40 Hz), but not other frequencies, reduces levels of amyloid-ß (Aß)1-40 and Aß 1-42 isoforms. Gene expression profiling revealed induction of genes associated with morphological transformation of microglia, and histological analysis confirmed increased microglia co-localization with Aß. Subsequently, we designed a non-invasive 40 Hz light-flickering regime that reduced Aß1-40 and Aß1-42 levels in the visual cortex of pre-depositing mice and mitigated plaque load in aged, depositing mice. Our findings uncover a previously unappreciated function of gamma rhythms in recruiting both neuronal and glial responses to attenuate Alzheimer's-disease-associated pathology.
Subject(s)
Alzheimer Disease/metabolism , Alzheimer Disease/pathology , Amyloid/metabolism , Gamma Rhythm , Microglia/metabolism , Plaque, Amyloid/metabolism , Plaque, Amyloid/prevention & control , Alzheimer Disease/physiopathology , Amyloid beta-Peptides/metabolism , Animals , CA1 Region, Hippocampal/drug effects , CA1 Region, Hippocampal/metabolism , Cell Shape/drug effects , Disease Models, Animal , Female , Gamma Rhythm/radiation effects , Interneurons/metabolism , Interneurons/radiation effects , Light , Male , Mice , Microglia/cytology , Microglia/radiation effects , Optogenetics , Parvalbumins/metabolism , Peptide Fragments/metabolism , Plaque, Amyloid/therapy , Transcriptome , Visual Cortex/physiology , Visual Cortex/radiation effectsABSTRACT
Kynurenic acid is a tryptophan metabolite that is synthesized and released in the brain by astrocytes and acts as an antagonist of nicotinic acetylcholine receptors and N-methyl-d-aspartate glutamate receptors, both of which are critically involved in cognition as well as neural plasticity and brain development. The concentration of kynurenic acid is increased in the brains of persons with schizophrenia and this increase has been implicated in the cognitive and social impairments associated with the disease. In addition, growing evidence suggests that the increase in kynurenic acid may begin early in life. For example, exposure to influenza A virus during development results in a transient increase in kynurenic acid concentration that could disrupt normal brain development and lead to cognitive deficits later in life. Changes in kynurenic acid may thus provide a link between developmental exposure to viruses and the increased risk of subsequently developing schizophrenia. To test this, we mimicked the effects of influenza A exposure by treating rats with kynurenine, the precursor of kynurenic acid, on postnatal days 7-10. We observed a transient increase in both kynurenic acid and quinolinic acid during treatment. When rats were subsequently behaviorally tested as adults, those previously treated with kynurenine exhibited decreased social behavior and locomotor activity. In contrast, attentional function and fear conditioning were not affected. Together with other recent findings, these data have several implications for understanding how viral-induced changes in tryptophan metabolism during development may contribute to schizophrenia-related symptoms later in life.
Subject(s)
Behavior, Animal/drug effects , Excitatory Amino Acid Antagonists/pharmacology , Kynurenic Acid/pharmacology , Quinolinic Acid/pharmacology , Analysis of Variance , Animals , Animals, Newborn , Attention/drug effects , Brain Chemistry/drug effects , Cohort Studies , Conditioning, Psychological/drug effects , Dose-Response Relationship, Drug , Fear/drug effects , Female , Interpersonal Relations , Motor Activity/drug effects , Pregnancy , Rats , Rats, Long-EvansABSTRACT
The retrosplenial cortex (RSP) is highly interconnected with medial temporal lobe structures, yet relatively little is known about its specific contributions to learning and memory. One possibility is that RSP is involved in forming associations between multiple sensory stimuli. Indeed, damage to RSP disrupts learning about spatial or contextual cues and also impairs learning about co-occurring conditioned stimuli (CSs). Two experiments were conducted to test this notion more rigorously. In Experiment 1, rats were trained in a serial feature negative discrimination task consisting of reinforced presentations of a tone alone and nonreinforced serial presentations of a light followed by the tone. Thus, in contrast to prior studies, this paradigm involved serial presentation of conditioned stimuli (CS), rather than simultaneous presentation. Rats with damage to RSP failed to acquire the discrimination, indicating that RSP is required for forming associations between sensory stimuli regardless of whether they occur serially or simultaneously. In Experiment 2, a sensory preconditioning task was used to determine if RSP was necessary for forming associations between stimuli even in the absence of reinforcement. During the first phase of this procedure, one auditory stimulus was paired with a light while a second auditory stimulus was presented alone. In the next phase of training, the same light was paired with food. During the final phase of the procedure both auditory stimuli were presented alone during a single session. Control, but not RSP-lesioned rats, exhibited more food cup behavior following presentation of the auditory cue that was previously paired with light compared with the unpaired auditory stimulus, indicating that a stimulus-stimulus association was formed during the first phase of training. These results support the idea that RSP has a fundamental role in forming associations between environmental stimuli.
