Biology subjects

Mitchell, A. S.

Publications and source records attributed to Mitchell, A. S..

7 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↗

bioRxiv2024

Connectivity in the human and the monkey brain probes causal involvement of the fornix in Mild Cognitive Impairment and Alzheimer's Disease

Alzheimers disease (AD) is characterised by memory loss and severe deficits in cognitive function associated with neural degeneration in a network of brain regions. However, little is known about those regions connectivity patterns and how that differs from mild cognitive impairment (MCI) or healthy aging. To address that, we used diffusion-weighted MRI to determine connectivity across 11 key memory-related regions and their unique set of connections (connectivity fingerprints) to 14 white matter (WM) tracts. One WM tract particularly important for memory, and attractive target for therapeutic interventions in AD, is the fornix. However, determining fornix-specific contributions to memory deficits or therapeutic benefits is difficult, partly because the fornix carries numerous subcortical and cortical projections. To explore that, we additionally examined MRI-derived connectivity across homologous structures in non-human primates before and after fornix transections. We report several important findings. First, that connectivity between the hippocampus and the anterior thalamus (ATh) is strongly compromised in cognitive decline, as is fornix integrity. We also found strong reductions in the hippocampus-fornix and ATh-fornix connectivity in AD, demonstrating that fingerprint divergence across groups in hippocampal CA1 and ATh can identify differences between people with AD and MCI. In AD, we observed also elevated connectivity between WM tracts and the hippocampus or the ATh, suggesting a compensatory mechanism, which, importantly, depends on a viable fornix. We finally demonstrate that certain thalamic nuclei and hippocampal subfields link through the retrosplenial cortex in both species, highlighting its potential role as an alternative target for interventions in memory disorders.

neuroscience↗

bioRxiv2021

Evidence for two distinct thalamocortical circuits in retrosplenial cortex

Retrosplenial cortex (RSC) lies at the interface between perceptual and memory networks in the brain and mediates between these, although it is not yet known how. It has two distinct subregions, granular (gRSC) and dysgranular (dRSC). The present study investigated how these subregions differ with respect to their electrophysiology and connections, as a step towards understanding their functions. gRSC is more closely connected to the hippocampal system, in which theta-band local field potential oscillations are prominent. We therefore compared theta-rhythmic single-unit activity between the two RSC subregions and found, mostly in gRSC, a subpopulation of non-directional cells with spiking activity strongly entrained by theta oscillations, suggesting a stronger coupling of gRSC to the hippocampal system. We then used retrograde tracers to examine whether differences in neural coding between RSC subregions might reflect differential inputs from the anterior thalamus, which is a prominent source of RSC afferents. We found that gRSC and dRSC differ in their afferents from two AV subfields: dorsomedial (AVDM) and ventrolateral (AVVL). AVVL targets both gRSC and dRSC, while AVDM provides a selective projection to gRSC. These combined results suggest the existence of two distinct but interacting RSC subcircuits: one connecting AVDM to gRSC that may comprise part of the cognitive hippocampal system, and the other connecting AVVL to both RSC regions that may link hippocampal and perceptual regions. We suggest that these subcircuits are distinct to allow for differential weighting during integration of converging sensory and cognitive computations: an integration that may take place in thalamus, RSC or both. HighlightsO_LIThe two retrosplenial cortex subregions, gRSC and dRSC, differ in their temporal firing characteristics and relation to theta oscillations. C_LIO_LIThere are differential afferents from the anteroventral thalamic nucleus to gRSC and dRSC, with the dorsomedial subnucleus projecting selectively to gRSC. C_LIO_LIThe anteroventral thalamus-retrosplenial cortex circuitry thus comprises two functionally and anatomically distinct but connected circuits, differentially connected to the hippocampal system, that may support the integration of cognitive and perceptual information. C_LI

neuroscience↗

bioRxiv2021

Mediodorsal thalamus is critical for updating during extra-dimensional shifts but not reversals in the attentional set-shifting task

Cognitive flexibility, attributed to frontal cortex, is vital for navigating the complexities of everyday life. The mediodorsal thalamus (MD), interconnected to frontal cortex, may influence cognitive flexibility. Here male rats performed an attentional set-shifting task measuring intra-dimensional and extra-dimensional shifts in sensory discriminations. MD lesion rats needed more trials to learn the rewarded sensory dimension. However, once the choice response strategy was established, learning further two-choice discriminations in the same sensory dimension, and reversals of the reward contingencies in the same dimension, were unimpaired. Critically though, MD lesion rats were impaired during the extra-dimensional shift, when they must rapidly update the optimal choice response strategy. Behavioral analyses showed MD lesion rats had significantly reduced correct within trial second choice responses. This evidence shows transfer of information via the MD is critical when monitoring and rapid within trial updates in established choice response strategies are required after there is a rule change. Significance statementWe demonstrate for the first time that rodent mediodorsal (MD) thalamus is a critical node when choice response strategies need to change rapidly after a within session rule change but not after reversals of reward contingencies during reward guided learning. MD interactions with orbitofrontal cortex are critical for value based learning, while MD interactions with medial prefrontal cortex are critical for rapid within trial updating of optimal choice response rules. MD interactions with the orbitofrontal cortex are not always necessary for reversal learning.

animal behavior and cognition↗

bioRxiv2018

Intact extrastriate visual network without primary visual cortex in a Rhesus macaque with naturally occurring Blindsight

Lesions of primate primary visual cortex (V1) lead to loss of conscious visual perception, and are often devastating to those affected. Understanding the neural consequences of such damage may aid the development of rehabilitation methods. In this rare case of a Rhesus macaque (monkey S), likely born without V1, we investigated the brain structures underlying residual visual abilities using multimodal magnetic resonance imaging. In-group behaviour was unremarkable. Compared to controls, visual structures outside of monkey Ss lesion appeared normal. Visual stimulation under anaesthesia with checkerboards activated lateral geniculate nucleus of monkey S, but not the pulvinar, while full-field moving dots activated the pulvinar. Functional connectivity analysis revealed a network of bilateral dorsal visual areas temporally correlated with V5/MT, consistent across lesion and control animals. Overall, we found an intact network of visual cortical areas even without V1, but little evidence for strengthened subcortical input to V5/MT supporting residual visual function.

neuroscience↗

bioRxiv2017

Functional reorganisation and recovery following cortical lesions: A study in macaque monkeys

Damage following traumatic brain injury or stroke can often extend beyond the boundaries of the initial insult and can lead to maladaptive cortical reorganisation. On the other hand, beneficial cortical reorganisation leading to recovery of function can also occur. Here, we used resting state FMRI (rsFMRI) to examine how functional connectivity in the macaque brain changed across time in response to lesions to the prefrontal cortex, and how this reorganisation correlated with changes in behaviour. Two monkeys were trained to perform location-based and object-based delayed match-to-sample tasks. We also collected rsFMRI data under general anaesthesia at two pre-lesion time-points, separated by 3-4 weeks. After two cycles of testing and scanning, the animals received a principal sulcus lesion followed by an additional 4 cycles of testing and scanning. Later, the same animals received a second lesion to the opposite hemisphere and additional cycles of testing and scanning.\n\nBoth animals showed a marked behavioural impairment following the first lesion, which was associated with a decrease in functional connectivity, predominantly within frontal-frontal networks in both hemispheres. Approximately 8 weeks following the lesion, performance improved, as did functional connectivity within these networks. Following the second lesion, functional connectivity again decreased and this was associated with a marginal behavioural deficit that did not recover.\n\nOur data show that behavioural impairments reflect not just the removal of the lesioned area, but also disturbance to an extensive cortical network. This network can recover by restoring and/or strengthening pre-existing connections, leading to improvement in behaviour.

neuroscience↗

bioRxiv2017

Retrosplenial cortex and its role in spatial cognition

Retrosplenial cortex (RSC) is a region within the posterior neocortical system, heavily interconnected with an array of brain networks, both cortical and subcortical, that is engaged by a myriad of cognitive tasks. Although there is no consensus as to its precise function, evidence from both human and animal studies clearly points to a role in spatial cognition. However, the spatial processing impairments that follow RSC damage are not straightforward to characterise, leading to difficulties in defining the exact nature of its role. In the present article we review this literature and classify the types of ideas that have been put forward into three broad, somewhat overlapping classes: (i) Learning of landmark location, stability and permanence; (ii) Integration between spatial reference frames, and (iii) Consolidation and retrieval of spatial knowledge (\"schemas\"). We evaluate these models and suggest ways to test them, before briefly discussing whether the spatial function may be a subset of a more general function in episodic memory.

animal behavior and cognition↗