A bridge between: Te Ao Māori and Te Ara Paerangi

Purpose Aotearoa New Zealand’s Research, Science and Innovation (RSI) system is undergoing a ‘once in a generation’ reform known as Te Ara Paerangi Future Pathways (TAP). One of TAP’s four high-level goals is to embed Te Tiriti o Waitangi across the RSI system. Using the analogy of bridge-making, we draw on insights from Māori submissions to TAP to identify collective Māori expectations for what a Tiriti-embedded system entails. Method Submissions were accessed through the document library on the Ministry of Business, Innovation and Employment website. 34 submissions from individuals and collectives were identified as Māori. Qualitative Document Analysis was used to identify major themes. Results Results are described with reference to basic bridge-building principles of design, foundations, materials and maintenance. Key thematic findings include: Māori, as Tiriti partners, must be meaningfully involved in the reform design; the RSI system’s foundations are deeply colonial - decolonisation is needed to value, respect and protect Māori knowledges and knowledge-holders; workforce development, infrastructure and policies are required to empower partnered and autonomous RSI approaches; and, ongoing system maintenance in the form of monitoring is required to ensure transparency, accountability and equitable benefits. Reflection Having committed to embedding Te Tiriti across the RSI system, MBIE now has a duty of care to deliver on its commitment vis-à-vis the National Research Priorities. This paper is a timely opportunity to set a baseline of collective expectations against which to assess the future efficacy of TAP. Ka mahi mātou, me te takune hei puananī We will work with the intent to travel freely in any directio

Descending Post-commissural Fornix Lesions Produce Impaired Spatial Working Memory in a 12-arm Maze

Memory is supported in the brain by a distributed neural network, comprised of cortical, limbic and brainstem structures and fibre pathways. The descending component of the post-commissural fornix (dPCFx) conveys hippocampal efferents to the mammillary bodies (MB), and so presents as a critical pathway along the hippocampal-MB-anterior thalamic axis, structures all crucial to memory function. However, two previous studies have reported surprisingly mild, if any, effect of selective dPCFx lesions on spatial memory in an 8-arm radial arm maze (RAM). To examine the impact of dPCFx lesions on electrophysiological activity in the anterior thalamus, dorsal hippocampus and prefrontal cortex, and in an effort to substantially increase task difficulty, we trained rats postoperatively in a 12-arm RAM. We found that dPCFx lesions produced a severe RAM impairment, showing that the RAM can elicit spatial working memory deficits after dPCFx lesions when task demands are high and suggesting that the dPCFx may indeed play an important mnemonic role

Anterior thalamic nuclei neurons sustain memory

A hippocampal-diencephalic-cortical network supports memory function. The anterior thalamic nuclei (ATN) form a key anatomical hub within this system. Consistent with this, injury to the mammillary body-ATN axis is associated with examples of clinical amnesia. However, there is only limited and indirect support that the output of ATN neurons actively enhances memory. Here, in rats, we first showed that mammillothalamic tract (MTT) lesions caused a persistent impairment in spatial working memory. MTT lesions also reduced rhythmic electrical activity across the memory system. Next, we introduced 8.5 Hz optogenetic theta-burst stimulation of the ATN glutamatergic neurons. The exogenously-triggered, regular pattern of stimulation produced an acute and substantial improvement of spatial working memory in rats with MTT lesions and enhanced rhythmic electrical activity. Neither behaviour nor rhythmic activity was affected by endogenous stimulation derived from the dorsal hippocampus. Analysis of immediate early gene activity, after the rats foraged for food in an open field, showed that exogenously-triggered ATN stimulation also increased Zif268 expression across memory-related structures. These findings provide clear evidence that increased ATN neuronal activity supports memory. They suggest that ATN-focused gene therapy may be feasible to counter clinical amnesia associated with dysfunction in the mammillary body-ATN axis

Striatal mRNA expression patterns underlying peak dose L-DOPA-induced dyskinesia in the 6-OHDA hemiparkinsonian rat

L-DOPA is the primary pharmacological treatment for relief of the motor symptoms of Parkinson’s disease (PD). With prolonged treatment (⩾5 years) the majority of patients will develop abnormal involuntary movements as a result of L-DOPA treatment, known as L-DOPA-induced dyskinesia. Understanding the underlying mechanisms of dyskinesia is a crucial step toward developing treatments for this debilitating side effect. We used the 6-hydroxydopamine (6-OHDA) rat model of PD treated with a three-week dosing regimen of L-DOPA plus the dopa decarboxylase inhibitor benserazide (4 mg/kg and 7.5 mg/kg s.c., respectively) to induce dyskinesia in 50% of individuals. We then used RNA-seq to investigate the differences in mRNA expression in the striatum of dyskinetic animals, non-dyskinetic animals, and untreated parkinsonian controls at the peak of dyskinesia expression, 60 min after L-DOPA administration. Overall, 255 genes were differentially expressed; with significant differences in mRNA expression observed between all three groups. In dyskinetic animals 129 genes were more highly expressed and 14 less highly expressed when compared with non-dyskinetic and untreated parkinsonian controls. In L-DOPA treated animals 42 genes were more highly expressed and 95 less highly expressed when compared with untreated parkinsonian controls. Gene set cluster analysis revealed an increase in expression of genes associated with the cytoskeleton and phosphoproteins in dyskinetic animals compared with non-dyskinetic animals, which is consistent with recent studies documenting an increase in synapses in dyskinetic animals. These genes may be potential targets for drugs to ameliorate L-DOPA-induced dyskinesia or as an adjunct treatment to prevent their occurrence

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