Hepatocellular senescence induces multi-organ senescence and dysfunction via TGFβ.

Cellular senescence is not only associated with ageing but also impacts physiological and pathological processes, such as embryonic development and wound healing. Factors secreted by senescent cells affect their microenvironment and can induce spreading of senescence locally. Acute severe liver disease is associated with hepatocyte senescence and frequently progresses to multi-organ failure.

Evidence for prodromal changes in neuronal excitability and neuroinflammation in the hippocampus in young alpha-synuclein (A30P) transgenic mice.

Introduction: Neuronal hyperexcitability and neuroinflammation are thought to occur at early stages in a range of neurodegenerative diseases. Neuroinflammation, notably activation of microglia, has been identified as a potential prodromal marker of dementia with Lewy bodies (DLB). Using a transgenic mouse model of DLB that over-expresses human mutant (A30P) alpha-synuclein (hα-syn) we have investigated whether early neuroinflammation is evident in the hippocampus in young pre-symptomatic animals.

Delineating mechanisms underlying parvalbumin neuron impairment in different neurological and neurodegenerative disorders: the emerging role of mitochondrial dysfunction.

Given the current paucity of effective treatments in many neurological disorders, delineating pathophysiological mechanisms among the major psychiatric and neurodegenerative diseases may fuel the development of novel, potent treatments that target shared pathways. Recent evidence suggests that various pathological processes, including bioenergetic failure in mitochondria, can perturb the function of fast-spiking, parvalbumin-positive neurons (PV+). These inhibitory neurons critically influence local circuit regulation, the generation of neuronal network oscillations and complex brain functioning.

AAV8 vector induced gliosis following neuronal transgene expression.

Introduction: Expression of light sensitive ion channels by selected neurons has been achieved by viral mediated transduction with gene constructs, but for this to have therapeutic uses, for instance in treating epilepsy, any adverse effects of viral infection on the cerebral cortex needs to be evaluated. Here, we assessed the impact of adeno-associated virus 8 (AAV8) carrying DNA code for a soma targeting light activated chloride channel/FusionRed (FR) construct under the CKIIa promoter.

Methods: Viral constructs were harvested from transfected HEK293 cells and purified.

A novel mouse model of mitochondrial disease exhibits juvenile-onset severe neurological impairment due to parvalbumin cell mitochondrial dysfunction.

Mitochondrial diseases comprise a common group of neurometabolic disorders resulting from OXPHOS defects, that may manifest with neurological impairments, for which there are currently no disease-modifying therapies. Previous studies suggest inhibitory interneuron susceptibility to mitochondrial impairment, especially of parvalbumin-expressing interneurons (PV). We have developed a mouse model of mitochondrial dysfunction specifically in PV cells via conditional Tfam knockout, that exhibited a juvenile-onset progressive phenotype characterised by cognitive deficits, anxiety-like behaviour, head-nodding, stargazing, ataxia, and reduced lifespan.

Expression of the schizophrenia associated gene in the early developing fetal human forebrain.

Introduction: The protein fasciculation and elongation zeta-1 (FEZ1) is involved in axon outgrowth but potentially interacts with various proteins with roles ranging from intracellular transport to transcription regulation. Gene association and other studies have identified as being directly, or indirectly, implicated in schizophrenia susceptibility. To explore potential roles in normal early human forebrain neurodevelopment, we mapped expression by region and cell type.

Clinical and Non-Clinical Cardiovascular Disease Associated Pathologies in Parkinson's Disease.

Despite considerable breakthroughs in Parkinson's disease (PD) research, understanding of non-motor symptoms (NMS) in PD remains limited. The lack of basic level models that can properly recapitulate PD NMS either in vivo or in vitro complicates matters. Even so, recent research advances have identified cardiovascular NMS as being underestimated in PD.

Modulation of circuit oscillations in the rat anterior cingulate cortex (ACC) in vitro by mGlu2 metabotropic glutamate receptors and alleviation of the effects of phencyclidine-induced NMDA-receptor hypofunction.

Aberrant cortical oscillations in the beta and gamma range are associated with symptoms of schizophrenia and other psychiatric conditions. We have thus investigated the ability of anterior cingulate cortex (ACC) in vitro to generate beta and gamma oscillations, and how these are affected by Group II metabotropic glutamate (mGlu) receptor activation and blockade of N-methyl-d-aspartate (NMDA) receptors. Activation of Group II mGlu receptors, and mGlu2 specifically, with orthosteric agonists reduced the power of both beta and gamma oscillations in ACC without a significant effect on oscillation peak frequencies.

Anti-Cholestatic Therapy with Obeticholic Acid Improves Short-Term Memory in Bile Duct-Ligated Mice.

Patients with cholestatic liver disease, including those with primary biliary cholangitis, can experience symptoms of impaired cognition or brain fog. This phenomenon remains unexplained and is currently untreatable. Bile duct ligation (BDL) is an established rodent model of cholestasis.

A Closed-Loop Optogenetic Platform.

Neuromodulation is an established treatment for numerous neurological conditions, but to expand the therapeutic scope there is a need to improve the spatial, temporal and cell-type specificity of stimulation. Optogenetics is a promising area of current research, enabling optical stimulation of genetically-defined cell types without interfering with concurrent electrical recording for closed-loop control of neural activity. We are developing an open-source system to provide a platform for closed-loop optogenetic neuromodulation, incorporating custom integrated circuitry for recording and stimulation, real-time closed-loop algorithms running on a microcontroller and experimental control via a PC interface.

Increased hippocampal excitability in miR-324-null mice.

MicroRNAs are non-coding RNAs that act to downregulate the expression of target genes by translational repression and degradation of messenger RNA molecules. Individual microRNAs have the ability to specifically target a wide array of gene transcripts, therefore allowing each microRNA to play key roles in multiple biological pathways. miR-324 is a microRNA predicted to target thousands of RNA transcripts and is expressed far more highly in the brain than in any other tissue, suggesting that it may play a role in one or multiple neurological pathways.

Hippocampal network hyperexcitability in young transgenic mice expressing human mutant alpha-synuclein.

Abnormal excitability in cortical networks has been reported in patients and animal models of Alzheimer's disease (AD), and other neurodegenerative conditions. Whether hyperexcitability is a core feature of alpha(α)-synucleinopathies, including dementia with Lewy bodies (DLB) is unclear. To assess this, we used two murine models of DLB that express either human mutant α-synuclein (α-syn) the hA30P, or human wild-type α-syn (hWT-α-syn) mice.

Early Disruption of Cortical Sleep-Related Oscillations in a Mouse Model of Dementia With Lewy Bodies (DLB) Expressing Human Mutant (A30P) Alpha-Synuclein.

Changes in sleep behavior and sleep-related cortical activity have been reported in conditions associated with abnormal alpha-synuclein (α-syn) expression, in particular Parkinson's disease (PD) and dementia with Lewy bodies (DLB). Notably, changes can occur in patients years before the onset of cognitive decline. Sleep-related network oscillations play a key role in memory function, but how abnormal α-syn impacts the generation of such activity is currently unclear.

Anti-inflammatory treatment rescues memory deficits during aging in nfkb1 mice.

Chronic inflammation is a common feature of many age-related conditions including neurodegenerative diseases such as Alzheimer's disease. Cellular senescence is a state of irreversible cell-cycle arrest, thought to contribute to neurodegenerative diseases partially via induction of a chronic pro-inflammatory phenotype. In this study, we used a mouse model of genetically enhanced NF-κB activity (nfκb1 ), characterized by low-grade chronic inflammation and premature aging, to investigate the impact of inflammaging on cognitive decline.

Electrical stimulation of the ventral tegmental area evokes sleep-like state transitions under urethane anaesthesia in the rat medial prefrontal cortex via dopamine D -like receptors.

The role of dopamine in regulating sleep-state transitions during, both natural sleep and under anaesthesia, is still unclear. Recording in vivo in the rat mPFC under urethane anaesthesia, we observed predominantly slow wave activity (SWA) of <1 Hz in the local field potential interrupted by occasional spontaneous transitions to a low-amplitude-fast (LAF) pattern of activity. During periods of SWA, transitions to LAF activity could be rapidly and consistently evoked by electrical stimulation of the ventral tegmental area (VTA).

Quantitative electroencephalography as a marker of cognitive fluctuations in dementia with Lewy bodies and an aid to differential diagnosis.

Objective: We investigated for quantitative EEG (QEEG) differences between Alzheimer's disease (AD), dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD) patients and healthy controls, and for QEEG signatures of cognitive fluctuations (CFs) in DLB.

Methods: We analysed eyes-closed, resting state EEGs from 18 AD, 17 DLB and 17 PDD patients with mild dementia, and 21 age-matched controls. Measures included spectral power, dominant frequency (DF), frequency prevalence (FP), and temporal DF variability (DFV), within defined EEG frequency bands and cortical regions.

Impaired Fast Network Oscillations and Mitochondrial Dysfunction in a Mouse Model of Alpha-synucleinopathy (A30P).

Intracellular accumulation of alpha-synuclein (α-syn) is a key pathological process evident in Lewy body dementias (LBDs), including Parkinson's disease dementia (PDD) and dementia with Lewy bodies (DLB). LBD results in marked cognitive impairments and changes in cortical networks. To assess the impact of abnormal α-syn expression on cortical network oscillations relevant to cognitive function, we studied changes in fast beta/gamma network oscillations in the hippocampus in a mouse line that over-expresses human mutant α-syn (A30P).

Hetereogeneity in Neuronal Intrinsic Properties: A Possible Mechanism for Hub-Like Properties of the Rat Anterior Cingulate Cortex during Network Activity.

The anterior cingulate cortex (ACC) is vital for a range of brain functions requiring cognitive control and has highly divergent inputs and outputs, thus manifesting as a hub in connectomic analyses. Studies show diverse functional interactions within the ACC are associated with network oscillations in the β (20-30 Hz) and γ (30-80 Hz) frequency range. Oscillations permit dynamic routing of information within cortex, a function that depends on bandpass filter-like behavior to selectively respond to specific inputs.

Dorsal vs. ventral differences in fast Up-state-associated oscillations in the medial prefrontal cortex of the urethane-anesthetized rat.

Cortical slow oscillations (0.1-1 Hz), which may play a role in memory consolidation, are a hallmark of non-rapid eye movement (NREM) sleep and also occur under anesthesia. During slow oscillations the neuronal network generates faster oscillations on the active Up-states and these nested oscillations are particularly prominent in the PFC.

Subregional differences in the generation of fast network oscillations in the rat medial prefrontal cortex (mPFC) in vitro.

Key Points: Fast network oscillations in the beta (20-30 Hz) frequency range can be evoked with combined activation of muscarinic and kainate receptors in different subregions of the medial prefrontal cortex (mPFC). Subregional differences were observed as the oscillations in the dorsal prelimbic cortex (PrL) were smaller in magnitude than those in the ventral dorsopeduncular (DP) region, and these differences persisted in trimmed slices containing only PrL and DP regions. Oscillations in both regions were dependent upon GABAA and AMPA receptor activation but NMDA receptor blockade decreased oscillations only in the DP region.

Minimal size of cell assemblies coordinated by gamma oscillations.

In networks of excitatory and inhibitory neurons with mutual synaptic coupling, specific drive to sub-ensembles of cells often leads to gamma-frequency (25-100 Hz) oscillations. When the number of driven cells is too small, however, the synaptic interactions may not be strong or homogeneous enough to support the mechanism underlying the rhythm. Using a combination of computational simulation and mathematical analysis, we study the breakdown of gamma rhythms as the driven ensembles become too small, or the synaptic interactions become too weak and heterogeneous.

Multiple origins of the cortical γ rhythm.

Gamma rhythms (30-80 Hz) are a near-ubiquitous feature of neuronal population activity in mammalian cortices. Their dynamic properties permit the synchronization of neuronal responses to sensory input within spatially distributed networks, transient formation of local neuronal "cell assemblies," and coherent response patterns essential for intercortical regional communication. Each of these phenomena form part of a working hypothesis for cognitive function in cortex.

Partial loss of parvalbumin-containing hippocampal interneurons in dementia with Lewy bodies.

Dementia with Lewy bodies (DLB) is the second most common neurodegenerative dementia. Among many other neuropathological changes in DLB, brain region-specific cellular deficits have been reported. They include decreases in motor neuron and pyramidal cell densities, while neocortical parvalbumin (parv)-containing neurons are thought to be free of Lewy bodies and spared in DLB.

Cholinergic neuromodulation controls directed temporal communication in neocortex in vitro.

Acetylcholine is the primary neuromodulator involved in cortical arousal in mammals. Cholinergic modulation is involved in conscious awareness, memory formation and attention - processes that involve intercommunication between different cortical regions. Such communication is achieved in part through temporal structuring of neuronal activity by population rhythms, particularly in the beta and gamma frequency ranges (12-80 Hz).