Healthy lifestyles and wellbeing reduce neuroinflammation and prevent neurodegenerative and psychiatric disorders.

Since the mid-20th century, Western societies have considered productivity and economic outcomes are more important than focusing on people's health and wellbeing. This focus has created lifestyles with high stress levels, associated with overconsumption of unhealthy foods and little exercise, which negatively affect people's lives, and subsequently lead to the development of pathologies, including neurodegenerative and psychiatric disorders. Prioritizing a healthy lifestyle to maintain wellbeing may slow the onset or reduce the severity of pathologies. It is a win-win for everyone; for societies and for individuals. A balanced lifestyle is increasingly being adopted globally, with many doctors encouraging meditation and prescribing non-pharmaceutical interventions to treat depression. In psychiatric and neurodegenerative disorders, the inflammatory response system of the brain (neuroinflammation) is activated. Many risks factors are now known to be linked to neuroinflammation such as stress, pollution, and a high saturated and trans fat diet. On the other hand, many studies have linked healthy habits and anti-inflammatory products with lower levels of neuroinflammation and a reduced risk of neurodegenerative and psychiatric disorders. Sharing risk and protective factors is critical so that individuals can make informed choices that promote positive aging throughout their lifespan. Most strategies to manage neurodegenerative diseases are palliative because neurodegeneration has been progressing silently for decades before symptoms appear. Here, we focus on preventing neurodegenerative diseases by adopting an integrated "healthy" lifestyle approach. This review summarizes the role of neuroinflammation on risk and protective factors of neurodegenerative and psychiatric disorders.

Oscillatory waveform sharpness asymmetry changes in motor thalamus and motor cortex in a rat model of Parkinson's disease.

Parkinson's disease (PD) causes bursty and oscillatory activity in basal ganglia output that is thought to contribute to movement deficits through impact on motor thalamus and motor cortex (MCx). We examined the effect of dopamine loss on motor thalamus and motor cortex activity by recording neuronal and LFP activities in ventroanterior-ventrolateral (VAVL) thalamus and MCx in urethane-anesthetised control and parkinsonian rats. Dopamine lesion decreased the firing rate and increased the bursting of putative pyramidal neurons in layer V, but not layer VI, of the MCx without changing other aspects of firing pattern. In contrast, dopamine lesion did not affect VAVL firing rate, pattern or low threshold calcium spike bursts. Slow-wave (~1 Hz) oscillations in LFP recordings were analyzed with conventional power and waveform shape analyses. While dopamine lesion did not influence total power, it was consistently associated with an increase in oscillatory waveform sharpness asymmetry (i.e., sharper troughs vs. peaks) in both motor thalamus and MCx. Furthermore, we found that measures of sharpness asymmetry were positively correlated in paired motor thalamus-MCx recordings, and that correlation coefficients were larger in dopamine lesioned rats. These data support the idea that dysfunctional MCx activity in parkinsonism emerges from subsets of cell groups (e.g. layer V pyramidal neurons) and is evident in the shape but not absolute power of slow-wave oscillations. Hypoactive layer V pyramidal neuron firing in dopamine lesioned rats is unlikely to be driven by VAVL thalamus and may, therefore, reflect the loss of mesocortical dopaminergic afferents and/or changes in intrinsic excitability.

Reducing neuroinflammation via therapeutic compounds and lifestyle to prevent or delay progression of Parkinson's disease.

Parkinson's disease (PD) is the second most common age-associated neurodegenerative disorder and is characterised by progressive loss of dopamine neurons in the substantia nigra. Peripheral immune cell infiltration and activation of microglia and astrocytes are observed in PD, a process called neuroinflammation. Neuroinflammation is a fundamental response to protect the brain but, when chronic, it triggers neuronal damage. In the last decade, central and peripheral inflammation were suggested to occur at the prodromal stage of PD, sustained throughout disease progression, and may play a significant role in the pathology. Understanding the pathological mechanisms of PD has been a high priority in research, primarily to find effective treatments once symptoms are present. Evidence indicates that early life exposure to neuroinflammation as a consequence of life events, environmental or behaviour factors such as exposure to infections, pollution or a high fat diet increase the risk of developing PD. Many studies show healthy habits and products that decrease neuroinflammation also reduce the risk of PD. Here, we aim to stimulate discussion about the role of neuroinflammation in PD onset and progression. We highlight that reducing neuroinflammation throughout the lifespan is critical for preventing idiopathic PD, and present epidemiological studies that detail risk and protective factors. It is possible that introducing lifestyle changes that reduce neuroinflammation at the time of PD diagnosis may slow symptom progression. Finally, we discuss compounds and therapeutics to treat the neuroinflammation associated with PD.

A schizophrenia risk factor induces marked anatomical deficits at GABAergic-dopaminergic synapses in the rat ventral tegmental area: Essential evidence for new targeted therapies.

To develop new therapies for schizophrenia, evidence accumulated over decades highlights the essential need to investigate the GABAergic synapses that presynaptically influence midbrain dopaminergic neurons. Since current technology restricts these studies to animals, and evidence accumulated in recent decades indicates a developmental origin of schizophrenia, we investigated synaptic changes in male rat offspring exposed to maternal immune activation (MIA), a schizophrenia risk factor. Using a novel combination of lentiviruses, peroxidase-immunogold double labeling, three-dimensional serial section transmission electron microscopy and stereology, we observed clear anatomical alterations in synaptic inputs on dopaminergic neurons in the midbrain posterior ventral tegmental area (pVTA). These changes relate directly to a characteristic feature of schizophrenia: increased dopamine release. In 3-month-old and 14-month-old MIA rats, we found a marked decrease in the volume of presynaptic GABAergic terminals from the rostromedial tegmental nucleus (RMTg) and in the length of the synapses they made, when innervating pVTA dopaminergic neurons. In MIA rats in the long-term, we also discovered a decrease in the volume of the postsynaptic density (PSD) and in the maximum thickness of the PSD at the same synapses. These marked deficits were evident in conventional GABA-dopamine synapses and in synaptic triads that we discovered involving asymmetric synapses that innervated RMTg GABAergic presynaptic terminals, which in turn innervated pVTA dopaminergic neurons. In triads, the PSD thickness of asymmetric synapses was significantly decreased in MIA rats in the long-term cohort. The extensive anatomical deficits provide a potential basis for new therapies targeted at synaptic inputs on midbrain pVTA dopaminergic neurons, in contrast to current striatum-targeted antipsychotic drugs.

Throwing open the doors of perception: The role of dopamine in visual processing.

Animals form associations between visual cues and behaviours. Although dopamine is known to be critical in many areas of the brain to bind sensory information with appropriate responses, dopamine's role in the visual system is less well understood. Visual signals, which indicate the likely occurrence of a rewarding or aversive stimulus or indicate the context within which such stimuli may arrive, modulate activity in the superior colliculus and alter behaviour. However, such signals primarily originate in cortical and basal ganglia circuits, and evidence of direct signalling from midbrain dopamine neurons to superior colliculus is lacking. Instead, hypothalamic A13 dopamine neurons innervate the superior colliculus, and dopamine receptors are differentially expressed in the superior colliculus, with D1 receptors in superficial layers and D2 receptors in deep layers. However, it remains unknown if A13 dopamine neurons control behaviours through their effect on afferents within the superior colliculus. We propose that A13 dopamine neurons may play a critical role in processing information in the superior colliculus, modifying behavioural responses to visual cues, and propose some testable hypotheses regarding dopamine's effect on visual perception.

Role and Mechanism of Vitamin A Metabolism in the Pathophysiology of Parkinson's Disease.

Evidence shows that altered retinoic acid signaling may contribute to the pathogenesis and pathophysiology of Parkinson's disease (PD). Retinoic acid is the bioactive derivative of the lipophilic vitamin A. Vitamin A is involved in several important homeostatic processes, such as cell differentiation, antioxidant activity, inflammation and neuronal plasticity. The role of vitamin A and its derivatives in the pathogenesis and pathophysiology of neurodegenerative diseases, and their potential as therapeutics, has drawn attention for more than 10 years. However, the literature sits in disparate fields. Vitamin A could act at the crossroad of multiple environmental and genetic factors of PD. The purpose of this review is to outline what is known about the role of vitamin A metabolism in the pathogenesis and pathophysiology of PD. We examine key biological systems and mechanisms that are under the control of vitamin A and its derivatives, which are (or could be) exploited for therapeutic potential in PD: the survival of dopaminergic neurons, oxidative stress, neuroinflammation, circadian rhythms, homeostasis of the enteric nervous system, and hormonal systems. We focus on the pivotal role of ALDH1A1, an enzyme expressed by dopaminergic neurons for the detoxification of these neurons, which is under the control of retinoic acid. By providing an integrated summary, this review will guide future studies on the potential role of vitamin A in the management of symptoms, health and wellbeing for PD patients.

Primary motor cortex in Parkinson's disease: Functional changes and opportunities for neurostimulation.

Movement abnormalities of Parkinson's disease (PD) arise from disordered neural activity in multiple interconnected brain structures. The planning and execution of movement requires recruitment of a heterogeneous collection of pyramidal projection neurons in the primary motor cortex (M1). The neural representations of movement in M1 single-cell and field potential recordings are directly and indirectly influenced by the midbrain dopaminergic neurons that degenerate in PD. This review examines M1 functional alterations in PD as uncovered by electrophysiological recordings and neurostimulation studies in patients and experimental animal models. Dysfunction of the parkinsonian M1 depends on the severity and/or duration of dopamine-depletion and the species examined, and is expressed as alterations in movement-related firing dynamics; functional reorganisation of local circuits; and changes in field potential beta oscillations. Neurostimulation methods that modulate M1 activity directly (e.g., transcranial magnetic stimulation) or indirectly (subthalamic nucleus deep brain stimulation) improve motor function in PD patients, showing that targeted neuromodulation of M1 is a realistic therapy. We argue that the therapeutic profile of M1 neurostimulation is likely to be greatly enhanced with alternative technologies that permit cell-type specific control and incorporate feedback from electrophysiological biomarkers measured locally.

Aging in New Zealand: Ka haere ki te ao pakeketanga.

Aotearoa-New Zealand is expecting the number of older adults to double in the next 20 years. Despite publicly funded health and welfare support for older citizens, the aging experience differs across ethnic groups. This creates opportunities and challenges for health and social services to deliver culturally safe and equitable care for all older New Zealanders. Longitudinal and large data sets are pivotal for characterizing the aging experience from birth to advanced age. The New Zealand research funding system responded to predicted demographic changes by increasing funding in order to inform and address key health and well-being issues for older people. In addition, government strategies and policies increasingly focus on social aspects of aging and health inequities and require researchers and organizations to be better connected to end-users. New Zealand needs to continue to fund research that identifies unique and courageous service delivery solutions that result in positive social, financial, psychological, and physical aging for older New Zealanders.

Altered Recruitment of Motor Cortex Neuronal Activity During the Grasping Phase of Skilled Reaching in a Chronic Rat Model of Unilateral Parkinsonism.

Parkinson's disease causes prominent difficulties in the generation and execution of voluntary limb movements, including regulation of distal muscles and coordination of proximal and distal movement components to achieve accurate grasping. Difficulties with manual dexterity have a major impact on activities of daily living. We used extracellular single neuron recordings to investigate the neural underpinnings of parkinsonian movement deficits in the motor cortex of chronic unilateral 6-hydroxydopamine lesion male rats performing a skilled reach-to-grasp task the. Both normal movements and parkinsonian deficits in this task have striking homology to human performance. In lesioned animals there were several differences in the activity of cortical neurons during reaches by the affected limb compared with control rats. These included an increase in proportions of neurons showing rate decreases, along with increased amplitude of their average rate-decrease response at specific times during the reach, suggesting a shift in the balance of net excitation and inhibition of cortical neurons; a significant increase in the duration of rate-increase responses, which could result from reduced coupling of cortical activity to specific movement components; and changes in the timing and incidence of neurons with pure rate-increase or biphasic responses, particularly at the end of reach when grasping would normally be occurring. The changes in cortical activity may account for the deficits that occur in skilled distal motor control following dopamine depletion, and highlight the need for treatment strategies targeted toward modulating cortical mechanisms for fine distal motor control in patients.SIGNIFICANCE STATEMENT We show for the first time in a chronic lesion rat model of Parkinson's disease movement deficits that there are specific changes in motor cortex neuron activity associated with the grasping phase of a skilled motor task. Such changes provide a possible mechanism underpinning the problems with manual dexterity seen in Parkinson's patients and highlight the need for treatment strategies targeted toward distal motor control.

A neuroscience perspective of the gut theory of Parkinson's disease.

Parkinson's disease is caused by complex interactions between environmental factors and a genetic predisposition. Environmental factors include exposure to pesticides and toxins, heavy metals and accumulation of iron and/or manganese in the brain. However, accumulating evidence indicates that gut-brain health and function are impaired in Parkinson's disease, often a decade before motor symptoms are diagnosed. We present the gut-brain theory of Parkinson's disease and summarise the peripheral and central nervous system pathology, gastrointestinal symptoms experienced by many Parkinson's patients, the route by which gut-brain dysfunction may occur and changes in gut microbiota that are associated with disease expression. Finally, we consider future gut-based treatments to prevent or slow down the progression of Parkinson's disease and explore whether this knowledge may highlight biomarkers to be included in complex algorithms in the future to assess a person's risk of developing Parkinson's disease.

Viral vector-based tools advance knowledge of basal ganglia anatomy and physiology.

Viral vectors were originally developed to deliver genes into host cells for therapeutic potential. However, viral vector use in neuroscience research has increased because they enhance interpretation of the anatomy and physiology of brain circuits compared with conventional tract tracing or electrical stimulation techniques. Viral vectors enable neuronal or glial subpopulations to be labeled or stimulated, which can be spatially restricted to a single target nucleus or pathway. Here we review the use of viral vectors to examine the structure and function of motor and limbic basal ganglia (BG) networks in normal and pathological states. We outline the use of viral vectors, particularly lentivirus and adeno-associated virus, in circuit tracing, optogenetic stimulation, and designer drug stimulation experiments. Key studies that have used viral vectors to trace and image pathways and connectivity at gross or ultrastructural levels are reviewed. We explain how optogenetic stimulation and designer drugs used to modulate a distinct pathway and neuronal subpopulation have enhanced our mechanistic understanding of BG function in health and pathophysiology in disease. Finally, we outline how viral vector technology may be applied to neurological and psychiatric conditions to offer new treatments with enhanced outcomes for patients.

Marked differences in the number and type of synapses innervating the somata and primary dendrites of midbrain dopaminergic neurons, striatal cholinergic interneurons, and striatal spiny projection neurons in the rat.

Elucidating the link between cellular activity and goal-directed behavior requires a fuller understanding of the mechanisms underlying burst firing in midbrain dopaminergic neurons and those that suppress activity during aversive or non-rewarding events. We have characterized the afferent synaptic connections onto these neurons in the rat substantia nigra pars compacta (SNpc) and ventral tegmental area (VTA), and compared these findings with cholinergic interneurons and spiny projection neurons in the striatum. We found that the average absolute number of synapses was three to three and one-half times greater onto the somata of dorsal striatal spiny projection neurons than onto the somata of dopaminergic neurons in the SNpc or dorsal striatal cholinergic interneurons. A similar comparison between populations of dopamine neurons revealed a two times greater number of somatic synapses on VTA dopaminergic neurons than SNpc dopaminergic neurons. The percentage of symmetrical, presumably inhibitory, synaptic inputs on somata was significantly higher on spiny projection neurons and cholinergic interneurons compared with SNpc dopaminergic neurons. Synaptic data on the primary dendrites yielded similar significant differences for the percentage of symmetrical synapses for VTA dopaminergic vs. striatal neurons. No differences in the absolute number or type of somatic synapses were evident for dopaminergic neurons in the SNpc of Wistar vs. Sprague-Dawley rat strains. These data from identified neurons are pivotal for interpreting their electrophysiological responses to afferent activity and for generating realistic computer models of neuronal networks of striatal and midbrain dopaminergic function.

Lentiviral vectors as tools to understand central nervous system biology in mammalian model organisms.

Lentiviruses have been extensively used as gene delivery vectors since the mid-1990s. Usually derived from the human immunodeficiency virus genome, they mediate efficient gene transfer to non-dividing cells, including neurons and glia in the adult mammalian brain. In addition, integration of the recombinant lentiviral construct into the host genome provides permanent expression, including the progeny of dividing neural precursors. In this review, we describe targeted vectors with modified envelope glycoproteins and expression of transgenes under the regulation of cell-selective and inducible promoters. This technology has broad utility to address fundamental questions in neuroscience and we outline how this has been used in rodents and primates. Combining viral tract tracing with immunohistochemistry and confocal or electron microscopy, lentiviral vectors provide a tool to selectively label and trace specific neuronal populations at gross or ultrastructural levels. Additionally, new generation optogenetic technologies can be readily utilized to analyze neuronal circuit and gene functions in the mature mammalian brain. Examples of these applications, limitations of current systems and prospects for future developments to enhance neuroscience knowledge will be reviewed. Finally, we will discuss how these vectors may be translated from gene therapy trials into the clinical setting.

Patterned, but not tonic, optogenetic stimulation in motor thalamus improves reaching in acute drug-induced Parkinsonian rats.

High-frequency deep brain stimulation (DBS) in motor thalamus (Mthal) ameliorates tremor but not akinesia in Parkinson's disease. The aim of this study was to investigate whether there are effective methods of Mthal stimulation to treat akinesia. Glutamatergic Mthal neurons, transduced with channelrhodopsin-2 by injection of lentiviral vector (Lenti.CaMKII.hChR2(H134R).mCherry), were selectively stimulated with blue light (473 nm) via a chronically implanted fiber-optic probe. Rats performed a reach-to-grasp task in either acute drug-induced parkinsonian akinesia (0.03-0.07 mg/kg haloperidol, s.c.) or control (vehicle injection) conditions, and the number of reaches was recorded for 5 min before, during, and after stimulation. We compared the effect of DBS using complex physiological patterns previously recorded in the Mthal of a control rat during reaching or exploring behavior, with tonic DBS delivering the same number of stimuli per second (rate-control 6.2 or 1.8 Hz, respectively) and with stimulation patterns commonly used in other brain regions to treat neurological conditions (tonic 130 Hz, theta burst (TBS), and tonic 15 Hz rate-control for TBS). Control rats typically executed >150 reaches per 5 min, which was unaffected by any of the stimulation patterns. Acute parkinsonian rats executed <20 reaches, displaying marked akinesia, which was significantly improved by stimulating with the physiological reaching pattern or TBS (both p < 0.05), whereas the exploring and all tonic patterns failed to improve reaching. Data indicate that the Mthal may be an effective site to treat akinesia, but the pattern of stimulation is critical for improving reaching in parkinsonian rats.

Reduced reach-related modulation of motor thalamus neural activity in a rat model of Parkinson's disease.

Motor thalamus (Mthal) is a key node in the corticobasal ganglia (BG) loop that controls complex, cognitive aspects of movement. In Parkinson's disease (PD), profound alterations in neuronal activity occur in BG nuclei and cortex. Because Mthal is located between these two structures, altered Mthal activity has been assumed to underlie the pathogenesis of PD motor deficits. However, to date, inconsistent changes in neuronal firing rate and pattern have been reported in parkinsonian animals. Moreover, although a distinct firing pattern of Mthal neurons, called low-threshold calcium spike bursts (LTS bursts), is observed in reduced preparations, it remains unknown whether they occur or what their role might be in behaving animals. We recorded Mthal spiking activity in control and unilateral 6-hydroxydopamine lesioned rats performing a skilled forelimb-reaching task. We show for the first time that Mthal firing rate in control rats is modulated in a temporally precise pattern during reach-to-grasp movements, with a peak at the time of the reach-end and troughs just before and after it. We identified LTS-like events on the basis of LTS burst characteristics. These were rare, but also modulated, decreasing in incidence just after reach-end. The inhibitory modulations in firing rate and LTS-like events were abolished in parkinsonian rats. These data confirm that nigrostriatal dopamine depletion is accompanied by profound and specific deficits in movement-related Mthal activity. These changes would severely impair Mthal contributions to motor program development in motor cortex and are likely to be an important factor underlying the movement deficits of PD.

Motor thalamus integration of cortical, cerebellar and basal ganglia information: implications for normal and parkinsonian conditions.

Motor thalamus (Mthal) is implicated in the control of movement because it is strategically located between motor areas of the cerebral cortex and motor-related subcortical structures, such as the cerebellum and basal ganglia (BG). The role of BG and cerebellum in motor control has been extensively studied but how Mthal processes inputs from these two networks is unclear. Specifically, there is considerable debate about the role of BG inputs on Mthal activity. This review summarizes anatomical and physiological knowledge of the Mthal and its afferents and reviews current theories of Mthal function by discussing the impact of cortical, BG and cerebellar inputs on Mthal activity. One view is that Mthal activity in BG and cerebellar-receiving territories is primarily "driven" by glutamatergic inputs from the cortex or cerebellum, respectively, whereas BG inputs are modulatory and do not strongly determine Mthal activity. This theory is steeped in the assumption that the Mthal processes information in the same way as sensory thalamus, through interactions of modulatory inputs with a single driver input. Another view, from BG models, is that BG exert primary control on the BG-receiving Mthal so it effectively relays information from BG to cortex. We propose a new "super-integrator" theory where each Mthal territory processes multiple driver or driver-like inputs (cortex and BG, cortex and cerebellum), which are the result of considerable integrative processing. Thus, BG and cerebellar Mthal territories assimilate motivational and proprioceptive motor information previously integrated in cortico-BG and cortico-cerebellar networks, respectively, to develop sophisticated motor signals that are transmitted in parallel pathways to cortical areas for optimal generation of motor programmes. Finally, we briefly review the pathophysiological changes that occur in the BG in parkinsonism and generate testable hypotheses about how these may affect processing of inputs in the Mthal.

Beta frequency synchronization in basal ganglia output during rest and walk in a hemiparkinsonian rat.

Synchronized oscillatory neuronal activity in the beta frequency range has been observed in the basal ganglia of Parkinson's disease patients and hypothesized to be antikinetic. The unilaterally lesioned rat model of Parkinson's disease allows examination of this hypothesis by direct comparison of beta activity in basal ganglia output in non-lesioned and dopamine cell lesioned hemispheres during motor activity. Bilateral substantia nigra pars reticulata (SNpr) recordings of units and local field potentials (LFP) were obtained with EMG activity from the scapularis muscle in control and unilaterally nigrostriatal lesioned rats trained to walk on a rotary treadmill. After left hemispheric lesion, rats had difficulty walking contraversive on the treadmill but could walk in the ipsiversive direction. During inattentive rest, SNpr LFP power in the 12-25 Hz range (low beta) was significantly greater in the dopamine-depleted hemisphere than in non-lesioned and control hemispheres. During walking, low beta power was reduced in all hemispheres, while 25-40 Hz (high beta) activity was selectively increased in the lesioned hemisphere. High beta power increases were reduced by l-DOPA administration. SNpr spiking was significantly more synchronized with SNpr low beta LFP oscillations during rest and high beta LFP oscillations during walking in the dopamine-depleted hemispheres compared with non-lesioned hemispheres. Data show that dopamine loss is associated with opposing changes in low and high beta range SNpr activity during rest and walk and suggest that increased synchronization of high beta activity in SNpr output from the lesioned hemisphere during walking may contribute to gait impairment in the hemiparkinsonian rat.