ABSTRACT
Down syndrome (DS) is a genetic disorder caused by triplication of human chromosome 21. In addition to intellectual disability, DS is defined by a premature aging phenotype and Alzheimer's disease (AD) neuropathology, including septohippocampal circuit vulnerability and degeneration of basal forebrain cholinergic neurons (BFCNs). The Ts65Dn mouse model recapitulates key aspects of DS/AD pathology, namely age-associated atrophy of BFCNs and cognitive decline in septohippocampal-dependent behavioral tasks. We investigated whether maternal choline supplementation (MCS), a well-tolerated treatment modality, protects vulnerable BFCNs from age- and genotype-associated degeneration in trisomic offspring. We also examined the effect of trisomy, and MCS, on GABAergic basal forebrain parvalbumin neurons (BFPNs), an unexplored neuronal population in this DS model. Unbiased stereological analyses of choline acetyltransferase (ChAT)-immunoreactive BFCNs and parvalbumin-immunoreactive BFPNs were conducted using confocal z-stacks of the medial septal nucleus and the vertical limb of the diagonal band (MSN/VDB) in Ts65Dn mice and disomic (2N) littermates at 3-4 and 10-12 months of age. MCS trisomic offspring displayed significant increases in ChAT-immunoreactive neuron number and density compared to unsupplemented counterparts, as well as increases in the area of the MSN/VDB occupied by ChAT-immunoreactive neuropil. MCS also rescued BFPN number and density in Ts65Dn offspring, a novel rescue of a non-cholinergic cell population. Furthermore, MCS prevented age-associated loss of BFCNs and MSN/VDB regional area in 2N offspring, indicating genotype-independent neuroprotective benefits. These findings demonstrate MCS provides neuroprotection of vulnerable BFCNs and non-cholinergic septohippocampal BFPNs, indicating this modality has translational value as an early life therapy for DS, as well as extending benefits to the aging population at large.
Subject(s)
Alzheimer Disease , Basal Forebrain , Down Syndrome , Humans , Animals , Mice , Aged , Parvalbumins , GABAergic Neurons , Choline O-Acetyltransferase , Disease Models, Animal , Nerve Degeneration , Dietary Supplements , CholineABSTRACT
Psychiatric disorders that are characterized by impairments in sustained attention, including attention deficit hyperactivity disorder (ADHD), post-traumatic stress disorder (PTSD), and major depression are also sensitive to exacerbation by stress. Sustained attention relies on cholinergic and non-cholinergic projections from the nucleus basalis of Meynert (NBM) in the basal forebrain to the medial prefrontal cortex (mPFC). We have previously shown that central administration of the stress neuropeptide corticotropin releasing factor (CRF) impairs performance on the sustained attention task (SAT) in adult male and female rats. The present study investigated whether this effect was mediated by CRF's action in the NBM. Rats were administered CRF in the NBM and subsequent SAT performance was measured. A high dose of CRF (100 ng) significantly impaired performance on non-signaled events across sex. Because performance on non-signaled events is believed to depend on non-cholinergic (i.e., GABA and glutamate) signaling, high performance liquid chromatography was used to quantify amino acid levels in the NBM and mPFC. We found females have higher levels of glutamate, glutamine, GABA glycine, and alanine in the NBM than males. Importantly, CRF in the NBM led to a local decrease of taurine and several amino acids involved in glutamate synthesis in males and females, changes which may mediate the CRF-induced SAT performance deficit. Together these studies suggest that CRF regulation of amino acids in the NMB contributes to stress-induced attention deficits.
Subject(s)
Basal Nucleus of Meynert , Corticotropin-Releasing Hormone , Rats , Male , Female , Animals , Corticotropin-Releasing Hormone/metabolism , Glutamic Acid/metabolism , Taurine/metabolism , gamma-Aminobutyric Acid/metabolismABSTRACT
The ability to rapidly arouse from sleep is important for survival. However, increased arousals in patients with sleep apnea and other disorders prevent restful sleep and contribute to cognitive, metabolic, and physiologic dysfunction [1, 2]. Little is currently known about which neural systems mediate these brief arousals, hindering the development of treatments that restore normal sleep. The basal forebrain (BF) receives inputs from many nuclei of the ascending arousal system, including the brainstem parabrachial neurons, which promote arousal in response to elevated blood carbon dioxide levels, as seen in sleep apnea [3]. Optical inhibition of the terminals of parabrachial neurons in the BF impairs cortical arousals to hypercarbia [4], but which BF cell types mediate cortical arousals in response to hypercarbia or other sensory stimuli is unknown. Here, we tested the role of BF parvalbumin (PV) neurons in arousal using optogenetic techniques in mice. Optical stimulation of BF-PV neurons produced rapid transitions to wakefulness from non-rapid eye movement (NREM) sleep but did not affect REM-wakefulness transitions. Unlike previous studies of BF glutamatergic and cholinergic neurons, arousals induced by stimulation of BF-PV neurons were brief and only slightly increased total wake time, reminiscent of clinical findings in sleep apnea [5, 6]. Bilateral optical inhibition of BF-PV neurons increased the latency to arousal produced by exposure to hypercarbia or auditory stimuli. Thus, BF-PV neurons are an important component of the brain circuitry that generates brief arousals from sleep in response to stimuli, which may indicate physiological dysfunction or danger to the organism.
Subject(s)
Acoustic Stimulation , Arousal/physiology , Carbohydrates/administration & dosage , Neurons/physiology , Animal Feed/analysis , Animals , Basal Forebrain/physiology , Diet , Mice , Parvalbumins/metabolism , Sleep/physiology , Wakefulness/physiologyABSTRACT
The medial frontal cortex has been linked to voluntary action, but an explanation of why decisions to act emerge at particular points in time has been lacking. We show that, in macaques, decisions about whether and when to act are predicted by a set of features defining the animal's current and past context; for example, respectively, cues indicating the current average rate of reward and recent previous voluntary action decisions. We show that activity in two brain areas-the anterior cingulate cortex and basal forebrain-tracks these contextual factors and mediates their effects on behavior in distinct ways. We use focused transcranial ultrasound to selectively and effectively stimulate deep in the brain, even as deep as the basal forebrain, and demonstrate that alteration of activity in the two areas changes decisions about when to act.
Subject(s)
Basal Forebrain/physiology , Decision Making/physiology , Gyrus Cinguli/physiology , Acoustic Stimulation , Animals , Cues , Deep Brain Stimulation/methods , Functional Neuroimaging , Macaca , Magnetic Resonance Imaging , Male , Neural Pathways/physiology , Time Factors , Ultrasonic WavesABSTRACT
Down syndrome (DS), trisomy 21, is marked by intellectual disability and a premature aging profile including degeneration of the basal forebrain cholinergic neuron (BFCN) projection system, similar to Alzheimer's disease (AD). Although data indicate that perinatal maternal choline supplementation (MCS) alters the structure and function of these neurons in the Ts65Dn mouse model of DS and AD (Ts), whether MCS affects the molecular profile of vulnerable BFCNs remains unknown. We investigated the genetic signature of BFCNs obtained from Ts and disomic (2N) offspring of Ts65Dn dams maintained on a MCS diet (Ts+, 2N+) or a choline normal diet (ND) from mating until weaning, then maintained on ND until 4.4-7.5 months of age. Brains were then collected and prepared for choline acetyltransferase (ChAT) immunohistochemistry and laser capture microdissection followed by RNA extraction and custom-designed microarray analysis. Findings revealed upregulation of select transcripts in classes of genes related to the cytoskeleton (Tubb4b), AD (Cav1), cell death (Bcl2), presynaptic (Syngr1), immediate early (Fosb, Arc), G protein signaling (Gabarap, Rgs10), and cholinergic neurotransmission (Chrnb3) in Ts compared to 2N mice, which were normalized with MCS. Moreover, significant downregulation was seen in select transcripts associated with the cytoskeleton (Dync1h1), intracellular signaling (Itpka, Gng3, and Mlst8), and cell death (Ccng1) in Ts compared to 2N mice that was normalized with MCS. This study provides insight into genotype-dependent differences and the effects of MCS at the molecular level within a key vulnerable cell type in DS and AD.
Subject(s)
Basal Forebrain/metabolism , Choline/administration & dosage , Cholinergic Neurons/metabolism , Dietary Supplements , Down Syndrome/genetics , Down Syndrome/metabolism , Animals , Basal Forebrain/drug effects , Cholinergic Neurons/drug effects , Disease Models, Animal , Down Syndrome/drug therapy , Female , Gene Expression , Male , Mice , Mice, Inbred C57BL , Mice, Transgenic , PregnancyABSTRACT
Diabetes induces early sufferance in the cholinergic septo-hippocampal system, characterized by deficits in learning and memory, reduced hippocampal plasticity and abnormal pro-nerve growth factor (proNGF) release from hippocampal cells, all linked to dysfunctions in the muscarinic cholinergic modulation of hippocampal physiology. These alterations are associated with dysregulation of several cholinergic markers, such as the NGF receptor system and the acetylcholine biosynthetic enzyme choline-acetyl transferase (ChAT), in the medial septum and its target, the hippocampus. Controlled and repeated sensory stimulation by electroacupuncture has been proven effective in counteracting the consequences of diabetes on cholinergic system physiology in the brain. Here, we used a well-established Type 1 diabetes model, obtained by injecting young adult male rats with streptozotocin, to induce sufferance in the septo-hippocampal system. We then evaluated the effects of a 3-week treatment with low-frequency electroacupuncture on: (a) the expression and protein distribution of proNGF in the hippocampus, (b) the tissue distribution and content of NGF receptors in the medial septum, (c) the neuronal cholinergic and glial phenotype in the septo-hippocampal circuitry. Twice-a-week treatment with low-frequency electroacupuncture normalized, in both hippocampus and medial septum, the ratio between the neurotrophic NGF and its neurotoxic counterpart, the precursor proNGF. Electroacupuncture regulated the balance between the two major proNGF variants (proNGF-A and proNGF-B) at both gene expression and protein synthesis levels. In addition, electroacupuncture recovered to basal level the pro-neurotrophic NGF receptor tropomyosin receptor kinase-A content, down-regulated in medial septum cholinergic neurons by diabetes. Electroacupuncture also regulated ChAT content in medial septum neurons and its anterograde transport toward the hippocampus. Our data indicate that repeated sensory stimulation can positively affect brain circuits involved in learning and memory, reverting early impairment induced by diabetes development. Electroacupuncture could exert its effects on the septo-hippocampal cholinergic neurotransmission in diabetic rats, not only by rescuing the hippocampal muscarinic responsivity, as previously described, but also normalizing acetylcholine biosynthesis and NGF metabolism in the hippocampus.
Subject(s)
Cholinergic Neurons/metabolism , Diabetes Mellitus, Experimental/metabolism , Electroacupuncture , Hippocampus/metabolism , Septum of Brain/metabolism , Animals , Choline O-Acetyltransferase/metabolism , Male , Nerve Growth Factors/metabolism , Neural Pathways/metabolism , Protein Precursors/metabolism , Rats , Rats, Sprague-Dawley , Receptor, Nerve Growth Factor/metabolism , Treatment OutcomeABSTRACT
High-density electroencephalographic (hdEEG) recordings are widely used in human studies to determine spatio-temporal patterns of cortical electrical activity. How these patterns of activity are modulated by subcortical arousal systems is poorly understood. Here, we couple selective optogenetic stimulation of a defined subcortical cell-type, basal forebrain (BF) parvalbumin (PV) neurons, with hdEEG recordings in mice (Opto-hdEEG). Stimulation of BF PV projection neurons preferentially generated time-locked gamma oscillations in frontal cortices. BF PV gamma-frequency stimulation potently modulated an auditory sensory paradigm used to probe cortical function in neuropsychiatric disorders, the auditory steady-state response (ASSR). Phase-locked excitation of BF PV neurons in advance of 40 Hz auditory stimuli enhanced the power, precision and reliability of cortical responses, and the relationship between responses in frontal and auditory cortices. Furthermore, synchronization within a frontal hub and long-range cortical interactions were enhanced. Thus, phasic discharge of BF PV neurons changes cortical processing in a manner reminiscent of global workspace models of attention and consciousness.
Subject(s)
Auditory Perception/physiology , Basal Forebrain/physiology , Evoked Potentials, Auditory , Gamma Rhythm , Neurons/physiology , Acoustic Stimulation , Animals , Electroencephalography , Male , Mice , Mice, Transgenic , Neurons/metabolism , Optogenetics , Parvalbumins/metabolismABSTRACT
OBJECTIVE: Ascending Reticular Activating System (ARAS) has a key role in consciousness. The ARAS is a complex network consisting of a portion of the brainstem reticular formation, nonspecific thalamic nuclei, hypothalamus, Basal Forebrain (BF), and cerebral cortex. We examined the reconstruction method and features of the neural tract between the hypothalamus and the BF in normal subjects, using Diffusion Tensor Tractography (DTT). METHODS: Twenty-three healthy subjects were recruited. The ARAS between the hypothalamus and the BF was reconstructed by two Regions of Interest (ROIs): 1) seed ROI - the isolated green portion for the BF on the color map, 2) target ROI - the hypothalamus on the axial image. DTT parameters of the ARAS between the hypothalamus and the BF were examined. RESULTS: Among 46 hemispheres in 23 normal subjects, 24 hemispheres (52.2 %) were identified in the ARAS between the hypothalamus and the BF. The reconstructed ARAS between the hypothalamus and the BF connected from the hypothalamus to the commissural level and anteriorly through the anterior commissure and then reached the BF. CONCLUSION: Using DTT, the ARAS between the hypothalamus and the BF was identified in normal subjects. Because the hypothalamus and BF are related to the regulation of wakefulness and sleep, our reconstruction method and results would be useful in the research on sleep and wakefulness aspects of consciousness.
Subject(s)
Basal Forebrain/anatomy & histology , Brain Stem/anatomy & histology , Hypothalamus/anatomy & histology , Neural Pathways/anatomy & histology , Thalamic Nuclei/anatomy & histology , Adult , Consciousness/physiology , Diffusion Tensor Imaging/methods , Female , Humans , MaleABSTRACT
Glutamate transporter 1 (GLT1) is the main astrocytic transporter that shapes glutamatergic transmission in the brain. However, whether this transporter modulates sleep-wake regulatory neurons is unknown. Using quantitative immunohistochemical analysis, we assessed perisomatic GLT1 apposition with sleep-wake neurons in the male rat following 6 h sleep deprivation (SD) or following 6 h undisturbed conditions when animals were mostly asleep (Rest). We found that SD decreased perisomatic GLT1 apposition with wake-promoting orexin neurons in the lateral hypothalamus compared with Rest. Reduced GLT1 apposition was associated with tonic presynaptic inhibition of excitatory transmission to these neurons due to the activation of Group III metabotropic glutamate receptors, an effect mimicked by a GLT1 inhibitor in the Rest condition. In contrast, SD resulted in increased GLT1 apposition with sleep-promoting melanin-concentrating hormone (MCH) neurons in the lateral hypothalamus. Functionally, this decreased the postsynaptic response of MCH neurons to high-frequency synaptic activation without changing presynaptic glutamate release. The changes in GLT1 apposition with orexin and MCH neurons were reversed after 3 h of sleep opportunity following 6 h SD. These SD effects were specific to orexin and MCH neurons, as no change in GLT1 apposition was seen in basal forebrain cholinergic or parvalbumin-positive GABA neurons. Thus, within a single hypothalamic area, GLT1 differentially regulates excitatory transmission to wake- and sleep-promoting neurons depending on sleep history. These processes may constitute novel astrocyte-mediated homeostatic mechanisms controlling sleep-wake behavior.SIGNIFICANCE STATEMENT Sleep-wake cycles are regulated by the alternate activation of sleep- and wake-promoting neurons. Whether and how astrocytes can regulate this reciprocal neuronal activity are unclear. Here we report that, within the lateral hypothalamus, where functionally opposite wake-promoting orexin neurons and sleep-promoting melanin-concentrating hormone neurons codistribute, the glutamate transporter GLT1, mainly present on astrocytes, distinctly modulates excitatory transmission in a cell-type-specific manner and according to sleep history. Specifically, GLT1 is reduced around the somata of orexin neurons while increased around melanin-concentrating hormone neurons following sleep deprivation, resulting in different forms of synaptic plasticity. Thus, astrocytes can fine-tune the excitability of functionally discrete neurons via glutamate transport, which may represent novel regulatory mechanisms for sleep.
Subject(s)
Excitatory Amino Acid Transporter 2/metabolism , Hypothalamic Hormones/physiology , Melanins/physiology , Orexins/physiology , Pituitary Hormones/physiology , Sleep Deprivation/metabolism , Sleep Deprivation/physiopathology , Synaptic Transmission , Animals , Hypothalamus/physiopathology , Male , Neurons , Parasympathetic Nervous System/physiopathology , Rats , Rats, Sprague-Dawley , Rats, Wistar , Receptors, Metabotropic Glutamate/metabolism , Sleep/physiology , Wakefulness/physiology , gamma-Aminobutyric Acid/physiologyABSTRACT
The Ts65Dn mouse model of Down syndrome (DS) and Alzheimer's disease (AD) exhibits cognitive impairment and degeneration of basal forebrain cholinergic neurons (BFCNs). Our prior studies demonstrated that maternal choline supplementation (MCS) improves attention and spatial cognition in Ts65Dn offspring, normalizes hippocampal neurogenesis, and lessens BFCN degeneration in the medial septal nucleus (MSN). Here we determined whether (i) BFCN degeneration contributes to attentional dysfunction, and (ii) whether the attentional benefits of perinatal MCS are due to changes in BFCN morphology. Ts65Dn dams were fed either a choline-supplemented or standard diet during pregnancy and lactation. Ts65Dn and disomic (2N) control offspring were tested as adults (12-17months of age) on a series of operant attention tasks, followed by morphometric assessment of BFCNs. Ts65Dn mice demonstrated impaired learning and attention relative to 2N mice, and MCS significantly improved these functions in both genotypes. We also found, for the first time, that the number of BFCNs in the nucleus basalis of Meynert/substantia innominata (NBM/SI) was significantly increased in Ts65Dn mice relative to controls. In contrast, the number of BFCNs in the MSN was significantly decreased. Another novel finding was that the volume of BFCNs in both basal forebrain regions was significantly larger in Ts65Dn mice. MCS did not normalize any of these morphological abnormalities in the NBM/SI or MSN. Finally, correlational analysis revealed that attentional performance was inversely associated with BFCN volume, and positively associated with BFCN density. These results support the lifelong attentional benefits of MCS for Ts65Dn and 2N offspring and have profound implications for translation to human DS and pathology attenuation in AD.
Subject(s)
Attention , Basal Forebrain/pathology , Choline/administration & dosage , Dietary Supplements , Down Syndrome/prevention & control , Maternal Nutritional Physiological Phenomena , Animals , Basal Forebrain/growth & development , Cell Count , Cell Size , Cholinergic Neurons/pathology , Disease Models, Animal , Down Syndrome/pathology , Down Syndrome/psychology , Female , Male , Mice, Inbred C3H , Mice, Inbred C57BL , Mice, Transgenic , Mothers , Organ Size , Pregnancy , Random AllocationABSTRACT
Local field potentials (LFPs) are commonly thought to reflect the aggregate dynamics in local neural circuits around recording electrodes. However, we show that when LFPs are recorded in awake behaving animals against a distal reference on the skull as commonly practiced, LFPs are significantly contaminated by non-local and non-neural sources arising from the reference electrode and from movement-related noise. In a data set with simultaneously recorded LFPs and electroencephalograms (EEGs) across multiple brain regions while rats perform an auditory oddball task, we used independent component analysis (ICA) to identify signals arising from electrical reference and from volume-conducted noise based on their distributed spatial pattern across multiple electrodes and distinct power spectral features. These sources of distal electrical signals collectively accounted for 23-77% of total variance in unprocessed LFPs, as well as most of the gamma oscillation responses to the target stimulus in EEGs. Gamma oscillation power was concentrated in volume-conducted noise and was tightly coupled with the onset of licking behavior, suggesting a likely origin of muscle activity associated with body movement or orofacial movement. The removal of distal signal contamination also selectively reduced correlations of LFP/EEG signals between distant brain regions but not within the same region. Finally, the removal of contamination from distal electrical signals preserved an event-related potential (ERP) response to auditory stimuli in the frontal cortex and also increased the coupling between the frontal ERP amplitude and neuronal activity in the basal forebrain, supporting the conclusion that removing distal electrical signals unmasked local activity within LFPs. Together, these results highlight the significant contamination of LFPs by distal electrical signals and caution against the straightforward interpretation of unprocessed LFPs. Our results provide a principled approach to identify and remove such contamination to unmask local LFPs.
Subject(s)
Brain Waves , Brain/physiology , Signal Processing, Computer-Assisted , Acoustic Stimulation , Animals , Artifacts , Electroencephalography , Evoked Potentials, Auditory , Male , Multivariate Analysis , Rats, Long-EvansABSTRACT
Acteoside, also known as verbascoside or orobanchin, is a common compound found in many important medicinal plants including the Chinese herb Cistanche deserticola Y. C. Ma, which is used for its neuroprotective and memory enhancement properties. We have investigated the effects of acteoside using a senescent mouse model induced by a combination of chronic intraperitoneal administration of d-gal (60 mg/kg/day) and oral administration AlCl3 (5 mg/kg/day) once daily for 90 days. After 60 days, acteoside (30, 60, and 120 mg/kg/day) was orally administered once daily for 30 days. The memory enhancing effects of acteoside were evaluated using the Morris water maze test. The results showed that 30-120 mg/kg/day of acteoside reduced the escape latency in finding the platform, and increased the number of crossings of the platform. A 30-120 mg/kg/day of acteoside increased significantly the expression of nerve growth factor and tropomycin receptor kinase A mRNA and protein in the hippocampus, measured using real-time RT-PCR, immunohistochemical analysis, and western blotting. These results support the use of C. deserticola for memory enhancement and indicate that the effects of acteoside are induced via promotion of nerve growth factor and tropomycin receptor kinase A expression.
Subject(s)
Cognition Disorders/drug therapy , Glucosides/pharmacology , Memory Disorders/drug therapy , Memory/drug effects , Phenols/pharmacology , Administration, Oral , Aging , Aluminum Chloride , Aluminum Compounds , Animals , Chlorides , Cognition Disorders/chemically induced , Disease Models, Animal , Galactose , Hippocampus/drug effects , Hippocampus/metabolism , Memory Disorders/chemically induced , Mice , Nerve Growth Factors/metabolism , Nerve Growth Factors/pharmacology , Receptor, trkA/metabolismABSTRACT
This study was conducted to investigate the protective effects of sodium p-aminosalicylic acid (PAS-Na) on learning and memory via increasing the number of basal forebrain choline acetyltransferase (ChAT) neurons in manganese (Mn)-exposed rats. Male Sprague Dawley rats were divided into following groups: the normal control I, II, and III groups, the model I, II, and III groups, low- and high-dose PAS-Na treatment (L- and H-PAS) group, PAS-Na prevention (PAS-P) group, and PAS-Na treatment (PAS-T) group. The model I, II, and III groups, L- and H-PAS, and PAS-T groups received intraperitoneal (i.p.) injection of 15 mg/kg manganese chloride tetrahydrate (MnCl2·4H2O) for 3 or 12 weeks, while the normal control I, II, and III groups received i.p. injection of an equal volume of saline; L- and H-PAS and PAS-T groups received back subcutaneous (s.c.) injection of PAS-Na (100 and 200 mg/kg) for the next 5 or 6 weeks, whereas model I and II group received back s.c. injection of an equal volume of saline. However, PAS-P group received back s.c. injection of 200 mg/kg PAS-Na + i.p. injection of 15 mg/kg MnCl2·4H2O for 12 weeks. Mn exposure significantly reduced the ability of spatial learning and memory capability, while PAS-Na prevention recovered it. Mn decreased the number of ChAT-positive neurons in vertical limb nucleus of the basal forebrain diagonal band/horizontal limb nucleus of the basal forebrain diagonal band and ChAT protein activity and treatment or prevention with PAS-Na restored those comparable with control. In brief, our results showed that PAS-Na may have protective effects on learning and memory against Mn via increasing the number of ChAT-positive neurons and activity of ChAT protein.
Subject(s)
Aminosalicylic Acid/pharmacology , Choline O-Acetyltransferase/metabolism , Cognition Disorders/enzymology , Manganese Poisoning/enzymology , Neuroprotective Agents/pharmacology , Aminosalicylic Acid/therapeutic use , Animals , Basal Forebrain/drug effects , Basal Forebrain/enzymology , Cognition Disorders/drug therapy , Learning/drug effects , Male , Manganese Poisoning/drug therapy , Memory/drug effects , Neurons/drug effects , Neurons/enzymology , Neuroprotective Agents/therapeutic use , Rats, Sprague-DawleyABSTRACT
BACKGROUND: Delirium is a profound neuropsychiatric disturbance precipitated by acute illness. Although dementia is the major risk factor this has typically been considered a binary quantity (i.e., cognitively impaired versus cognitively normal) with respect to delirium risk. We used humans and mice to address the hypothesis that the severity of underlying neurodegenerative changes and/or cognitive impairment progressively alters delirium risk. METHODS: Humans in a population-based longitudinal study, Vantaa 85+, were followed for incident delirium. Odds for reporting delirium at follow-up (outcome) were modeled using random-effects logistic regression, where prior cognitive impairment measured by Mini-Mental State Exam (MMSE) (exposure) was considered. To address whether underlying neurodegenerative pathology increased susceptibility to acute cognitive change, mice at three stages of neurodegenerative disease progression (ME7 model of neurodegeneration: controls, 12 weeks, and 16 weeks) were assessed for acute cognitive dysfunction upon systemic inflammation induced by bacterial lipopolysaccharide (LPS; 100 µg/kg). Synaptic and axonal correlates of susceptibility to acute dysfunction were assessed using immunohistochemistry. RESULTS: In the Vantaa cohort, 465 persons (88.4 ± 2.8 years) completed MMSE at baseline. For every MMSE point lost, risk of incident delirium increased by 5% (p = 0.02). LPS precipitated severe and fluctuating cognitive deficits in 16-week ME7 mice but lower incidence or no deficits in 12-week ME7 and controls, respectively. This was associated with progressive thalamic synaptic loss and axonal pathology. CONCLUSION: A human population-based cohort with graded severity of existing cognitive impairment and a mouse model with progressing neurodegeneration both indicate that the risk of delirium increases with greater severity of pre-existing cognitive impairment and neuropathology.
Subject(s)
Axons/pathology , Cognition Disorders/pathology , Delirium/epidemiology , Inflammation/pathology , Synapses/pathology , Aged, 80 and over , Animals , Cognition Disorders/chemically induced , Cognition Disorders/complications , Cognition Disorders/diagnosis , Cognition Disorders/psychology , Delirium/complications , Delirium/diagnosis , Disease Models, Animal , Disease Progression , Finland/epidemiology , Hippocampus/drug effects , Hippocampus/pathology , Humans , Inflammation/chemically induced , Inflammation/psychology , Lipopolysaccharides , Longitudinal Studies , Male , Maze Learning , Mice , Psychiatric Status Rating Scales , Thalamus/drug effects , Thalamus/pathologyABSTRACT
Synchronous neuronal activity in the thalamocortical system is critical for a number of behaviorally relevant computations, but hypersynchrony can limit information coding and lead to epileptiform responses. In the somatosensory thalamus, afferent inputs are transformed by networks of reciprocally connected thalamocortical neurons in the ventrobasal nucleus (VB) and GABAergic neurons in the thalamic reticular nucleus (TRN). These networks can generate oscillatory activity, and studies in vivo and in vitro have suggested that thalamic oscillations are often accompanied by synchronous neuronal activity, in part mediated by widespread divergence and convergence of both reticulothalamic and thalamoreticular pathways, as well as by electrical synapses interconnecting TRN neurons. However, the functional organization of thalamic circuits and its role in shaping input-evoked activity patterns remain poorly understood. Here we show that optogenetic activation of cholinergic synaptic afferents evokes near-synchronous firing in mouse TRN neurons that is rapidly desynchronized in thalamic networks. We identify several mechanisms responsible for desynchronization: (1) shared inhibitory inputs in local VB neurons leading to asynchronous and imprecise rebound bursting; (2) TRN-mediated lateral inhibition that further desynchronizes firing in the VB; and (3) powerful yet sparse thalamoreticular connectivity that mediates re-excitation of the TRN but preserves asynchronous firing. Our findings reveal how distinct local circuit features interact to desynchronize thalamic network activity.
Subject(s)
Cerebral Cortex/physiology , Cholinergic Neurons/physiology , Electroencephalography Phase Synchronization/physiology , Nerve Net/physiology , Thalamus/physiology , Animals , Female , Male , Mice , Mice, Inbred C57BL , Mice, Transgenic , Organ Culture TechniquesABSTRACT
In addition to intellectual disability, individuals with Down syndrome (DS) exhibit dementia by the third or fourth decade of life, due to the early onset of neuropathological changes typical of Alzheimer's disease (AD). Deficient ontogenetic neurogenesis contributes to the brain hypoplasia and hypocellularity evident in fetuses and children with DS. A murine model of DS and AD (the Ts65Dn mouse) exhibits key features of these disorders, notably deficient ontogenetic neurogenesis, degeneration of basal forebrain cholinergic neurons (BFCNs), and cognitive deficits. Adult hippocampal (HP) neurogenesis is also deficient in Ts65Dn mice and may contribute to the observed cognitive dysfunction. Herein, we demonstrate that supplementing the maternal diet with additional choline (approximately 4.5 times the amount in normal rodent chow) dramatically improved the performance of the adult trisomic offspring in a radial arm water maze task. Ts65Dn offspring of choline-supplemented dams performed significantly better than unsupplemented Ts65Dn mice. Furthermore, adult hippocampal neurogenesis was partially normalized in the maternal choline supplemented (MCS) trisomic offspring relative to their unsupplemented counterparts. A significant correlation was observed between adult hippocampal neurogenesis and performance in the water maze, suggesting that the increased neurogenesis seen in the supplemented trisomic mice contributed functionally to their improved spatial cognition. These findings suggest that supplementing the maternal diet with additional choline has significant translational potential for DS.