Biology subjects

Dalrymple-Alford, J. C.

Publications and source records attributed to Dalrymple-Alford, J. C..

9 recordsLinked to original sources

bioRxiv2026

Noradrenergic administration improves cognitive flexibility even after glutamatergic damage in rat mediodorsal thalamus or thalamic nucleus reuniens

Cognitive flexibility, switching behaviour responses to changing task demands, is classically attributed to the prefrontal cortex. Prefrontal thalamocortical circuits from mediodorsal thalamus (MD) or thalamic nucleus reuniens (RE) are altered in neurological conditions with cognitive flexibility deficits. Interventions targeting thalamocortical interactions may offer therapeutic benefits. Using the attentional set-shifting task, we showed in rats that permanent lesions of MD or RE glutamatergic neurons caused dissociable cognitive flexibility deficits and that the selective 2-adrenoceptor antagonist, atipamezole improved cognitive flexibility. RE damaged rats were impaired on the first of three intradimensional shift (ID) subtasks involving responding to novel stimuli pairings linked to the sensory dimension that reliably predicts reward. In contrast, MD damaged rats had intact ID performance but were impaired in the extradimensional shift (ED) subtask, whereby after task demands change rats are required to make a rapid shift in attending to and adapting choice responses to novel stimuli pairings linked to the previously irrelevant sensory dimension. RE damage did not disrupt ED performance. Intraperitoneal injections of atipamezole (1mg/kg), given 30-min prior to retesting with novel stimuli pairings improved cognitive flexibility despite permanent thalamic damage. VGluT2 labelling in the anterior cingulate cortex indicated neural network downstream effects with MD damage producing increased labelling relative to Sham operated controls, while RE damage showed decreased labelling. These findings demonstrate the dissociable influence of MD and RE during cognitive flexibility and suggest the use of noradrenergic regulation as a potential therapeutic option to reduce this cognitive dysfunction.

neuroscience↗

bioRxiv2023

The thalamic reuniens is associated with consolidation of non-spatial memory too

The nucleus reuniens (RE) is situated in the midline thalamus and provides a key link between hippocampus and prefrontal cortex. This anatomical relationship positions the Re as an ideal candidate to facilitate memory consolidation. Evidence is, however, lacking whether this role extends beyond spatial memory and contextual fear memory, both of which are strongly associated with hippocampal function. We therefore trained intact male Long-Evans rats on an odour-trace-object paired-association task in which the explicit 10-second delay between paired items renders the task sensitive to hippocampal function. Neurons in the RE showed markedly increased immediate early gene (Zif268) activation when rats were re-tested for the previous non-spatial memory 25 days after acquisition training, relative to a group tested at 5-days post-acquisition, as well as a control group tested 25 days after acquisition but with a new pair of non-spatial stimuli, and home cage controls. The remote recall group also showed relatively augmented IEG expression in the superficial layers of the medial PFC (anterior cingulate cortex and prelimbic cortex). These findings support the conclusion that the RE is preferentially engaged during remote recall in this non-spatial task and thus has a role beyond spatial memory and contextual fear memory.

neuroscience↗

bioRxiv2023

Bridging Big Data: Procedures for Combining Non-equivalent Cognitive Measures from the ENIGMA Consortium

Investigators in neuroscience have turned to Big Data to address replication and reliability issues by increasing sample sizes, statistical power, and representativeness of data. These efforts unveil new questions about integrating data arising from distinct sources and instruments. We focus on the most frequently assessed cognitive domain - memory testing - and demonstrate a process for reliable data harmonization across three common measures. We aggregated global raw data from 53 studies totaling N = 10,505 individuals. A mega-analysis was conducted using empirical bayes harmonization to remove site effects, followed by linear models adjusting for common covariates. A continuous item response theory (IRT) model estimated each individuals latent verbal learning ability while accounting for item difficulties. Harmonization significantly reduced inter-site variance while preserving covariate effects, and our conversion tool is freely available online. This demonstrates that large-scale data sharing and harmonization initiatives can address reproducibility and integration challenges across the behavioral sciences. TeaserWe present a global effort to devise harmonization procedures necessary to meaningfully leverage big data.

neuroscience↗

bioRxiv2021

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. HighlightsO_LIThe mammillothalamic tract (MTT) supports neural activity in an extended memory system. C_LIO_LIOptogenetic activation of neurons in the anterior thalamus acutely improves memory after MTT lesions. C_LIO_LIRescued memory associates with system-wide neuronal activation and enhanced EEG. C_LIO_LIAnterior thalamus actively sustains memory and is a feasible therapeutic target. C_LI O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=103 SRC="FIGDIR/small/457615v1_ufig1.gif" ALT="Figure 1"> View larger version (30K): org.highwire.dtl.DTLVardef@662d61org.highwire.dtl.DTLVardef@2d520corg.highwire.dtl.DTLVardef@165c742org.highwire.dtl.DTLVardef@fcfb4b_HPS_FORMAT_FIGEXP M_FIG Optostimulation of anterior thalamus restores memory function after MTT lesions Created with BioRender.com C_FIG

neuroscience↗

bioRxiv2021

BIFURCATING NEURONS IN THE ANTERIOR THALAMIC NUCLEI

The anterior thalamic nuclei (ATN) form a nodal point within a distributed memory network. The conventional view of ATN function describes segregated efferents to different terminal regions. By contrast, we found that bifurcating neurons are common within the anteromedial nucleus (AM) of the ATN. A substantial proportion of AM neurons ([~]36% within a region of interest) showed collateral projections when one of two retrograde neurotracers, Cholera Toxin Subunit B (CTB) conjugated to either Alexa Fluor(R) 488 or 594, was placed in the medial prefrontal cortex (mPFC) or dorsal subiculum (dSub). A marked degree of collateralization ([~]20% AM neurons) was also found when neurotracers were placed in mPFC and caudal retrosplenial cortex (cRSC); about 10% showed collaterals when the cRSC was paired with either dSub or vHF; the fewest (6%) was found for mPFC paired with the ventral hippocampal formation (vHF). A generally similar range of percentages of bifurcating neurons was found in the adjacent nucleus reuniens (Re). Evidence that AM neurons project simultaneously to many distantly-located structures provides a new perspective on ATN function. These neurons would facilitate direct coordination among key neural structures to support memory and may explain the strong association between the ATN and diencephalic amnesia.

neuroscience↗

bioRxiv2021

Anterior thalamic nuclei: A critical substrate for non-spatial paired-associate memory

Injury or dysfunction in the anterior thalamic nuclei (ATN) may be the key contributory factor in many instances of diencephalic amnesia. Experimental ATN lesions impair spatial memory and temporal discriminations, but there is only limited support for a more general role in non-spatial memory. To extend evidence on the effects of ATN lesions, we examined the acquisition of bi-conditional associations between odour and object pairings presented in a runway, either with or without a temporal gap between these items. Intact adult male rats acquired both the no-trace and 10-second trace versions of this non-spatial task. Intact rats trained in the trace version showed elevated Zif268 activation in the dorsal CA1 of the hippocampus, suggesting that the temporal component recruited additional neural processing. ATN lesions completely blocked acquisition on both versions of this association-memory task. This deficit was not due to poor inhibition to non-rewarded cues or impaired sensory processing, because rats with ATN lesions were unimpaired in the acquisition of simple odour discriminations and simple object discriminations using similar task demands in the same apparatus. This evidence challenges the view that impairments in arbitrary paired-associate learning after ATN lesions require the use of multimodal spatial stimuli. It suggests that diencephalic amnesia associated with the ATN stems from degraded attention to stimulus-stimulus associations and their representation across a distributed memory system.

neuroscience↗

bioRxiv2020

Cognitive tests that identify high risk of conversion to dementia in Parkinson's disease.

BackgroundPeople with Parkinsons disease who meet criteria for mild cognitive impairment are at increased risk of dementia. It is not known which tests are more effective than others for identifying the risk of dementia. MethodsAt baseline, we assessed performance on 21 neuropsychological test measures spanning five cognitive domains in a prospective longitudinal study of 196 non-demented people with Parkinsons. Elastic net logistic regression was used to identify a pair of tests from each cognitive domain that best predicted conversion to dementia over a four year period. The optimal tests most predictive of dementia were also determined when mild cognitive impairment was derived from a logistic-regression classifier that used all 21 measures simultaneously. ResultsWith two tests per domain, the resulting mild cognitive impairment group (N=87/196) captured 44 of 51 individuals who converted to PDD; the out-of-sample relative risk of PDD was 8.0 (95% CI [4.3, 24]), similar to that achieved with the full battery (N=102/196, capturing 45/51, relative risk = 6.9). When selecting tests regardless of domain, there was strong evidence for three tests: Trail Making part B (Executive), Map Search (Attention), and CVLT-II word list acquisition (Episodic Memory). The logistic-regression classifier achieved an out-of-sample AUC of 0.90 [0.84, 0.96] and a relative risk of 12 [6, 39]. ConclusionsAn abbreviated selection of neuropsychological tests can identify non-demented patients who have a high relative risk of progression to PDD.

neuroscience↗

bioRxiv2020

Microstructural integrity of the major nuclei of the thalamus in Parkinson's disease

BackgroundPrevious research has shown an association between thalamus and cognition in Parkinsons disease (PD). ObjectivesTo investigate the microstructural integrity of the nuclei of the thalamus and relationship with cognition. MethodsLevel II Movement Disorder Society Task Force Criteria characterised patients with Parkinsons disease as cognitively normal (PDN, n=51); with mild cognitive impairment (PD-MCI, n=16) or with dementia (PDD, n=15). Twenty-three healthy control subjects were included for comparison. A k-means clustering approach segmented the thalamus into regions representing nine major nuclei. Volume, fractional anisotropy and mean diffusivity of nuclei were compared between cognitive groups and the relationship with cognitive domain z-scores investigated using hierarchical Bayesian regression models. ResultsThere was an overall progressive increase in mean diffusivity as cognition deteriorated (PDN: 1.4 {micro}m2/s (95% uncertainty interval [0.2, 2.7]), PDMCI: 2.4 {micro}m2/s [0.8,4.0], PDD: 4.5 {micro}m2/s [2.8, 6.3]). The largest increase was in the lateral dorsal nucleus (PDN: 0.3 {micro}m2/s [-6.7, 7.2], PDMCI: 5.4 {micro}m2/s [-4.7, 16.1], PDD: 14.8 {micro}m2/s [5.0, 25.0]). Fractional anisotropy showed minimal change between cognitive groups (PDN: 0.001 [-0.005, 0,007], PDMCI: -0.005 [-0.013, 0.003], PDD: -0.005 [-0.014, 0.003]). Increase in mean diffusivity of the thalamus is associated with a global decline in cognition, the magnitude of the effect was greatest in lateral dorsal nucleus. Fractional anisotropy only showed evidence of a relationship with cognitive domain scores in the lateral dorsal nucleus. ConclusionsThe relationship between lateral dorsal nucleus integrity and cognitive changes is likely due to its primary connectivity with frontal and temporal regions.

neuroscience↗

bioRxiv2019

Nanopore sequencing of the glucocerebrosidase (GBA) gene in a New Zealand Parkinsons disease cohort

IntroductionBi-allelic mutations in the gene for glucocerebrosidase (GBA) cause Gaucher disease, an autosomal recessive lysosomal storage disorder. Gaucher disease causing GBA mutations in the heterozygous state are also high risk factors for Parkinsons disease (PD). GBA analysis is challenging due to a related pseudogene and structural variations (SVs) that can occur at this locus. We have applied and refined a recently developed nanopore DNA sequencing method to analyze GBA variants in a clinically assessed New Zealand longitudinal cohort of PD. MethodWe examined amplicons encompassing the coding region of GBA (8.9kb) from 229 PD cases and 50 healthy controls using the GridION nanopore sequencing platform, and Sanger validation. ResultsWe detected 23 variants in 21 PD cases (9.2% of patients). We detected modest PD risk variant p.N409S (rs76763715) in one case, p.E365K (rs2230288) in 12 cases, and p.T408M (rs75548401) in seven cases, one of whom also had p.E365K. We additionally detected the possible risk variants p.R78C (rs146774384) in one case, p.D179H (rs147138516) in one case which occurred on the same haplotype as p.E365K, and one novel variant c.335C>T or p.(L335=), that potentially impacts splicing of GBA transcripts. Additionally, we found a higher prevalence of dementia among patients with GBA variants. ConclusionThis work confirmed the utility of nanopore sequencing as a high-throughput method to identify known and novel GBA variants, and to assign precise haplotypes. Our observations may contribute to improved understanding of the effects of variants on disease pathogenesis, and to the development of more targeted treatments.

genetics↗