Biology subjects

Craig, M. T.

Publications and source records attributed to Craig, M. T..

4 recordsLinked to original sources

bioRxiv2025

Neuroinflammation driven by TLR7 activation in mice results in a global inflammatory response driving circuit-specific changes in neuronal gene expression

Interactions between the brain and immune system play a key role in the aetiology of brain disorders, with inflammation emerging as a potential causal factor in subsets of major depressive disorder, particularly those resistant to treatment. The causal mechanisms through which immune activation can drive depressive symptoms remain elusive, limiting the ability to develop new targeted therapies. Using a mouse model of neuroinflammation, involving a TLR7/8 agonist, we found central and systemic inflammation alongside anhedonia-like behaviours, altered thalamostriatal signalling and infiltration of peripheral immune cells into the brain. Here, we sought to use combined whole-brain transcriptome and spatial transcriptomics approaches to determine whether Aldara-driven neuroinflammation resulted in consistent immune and neurobiological changes throughout the brain. We found evidence of strong immune activation throughout the brain, with astrocytes displaying a strong inflammatory profile that was relatively uniform throughout. However, we found that this global inflammatory signal led to regionally-specific changes in gene expression, particularly reduced expression of genes associated with synaptic function in brain areas underlying mood and anxiety, such as ventral striatum and amygdala. Our data suggest potential mechanisms through which astrocytes regulate neuronal function in response to inflammation.

neuroscience↗

bioRxiv2024

Anhedonic behaviour in a TLR7-driven neuroinflammation mouse model is associated with impaired thalamostriatal signalling and immune cell ingress into the brain

Inflammation is implicated in 25% of depression cases, yet limited access to human brain for mechanistic studies and scarce translational models have hindered the identification of neural circuits linking systemic inflammation to depressive symptoms such as reduced motivation and anhedonia. Leveraging both clinical and pre-clinical approaches, we combined neuroimaging in individuals with psoriatic disease, a systemic inflammatory condition frequently associated with depression, with neurophysiological, behavioural and immunological studies in a psoriasis mouse model exhibiting neuroinflammation. We found that increased inflammation had a robust association with both depression and fatigue in individuals with psoriatic disease. Across species, we found that inflammatory signalling disrupts thalamostriatal circuitry, a key component of the motivational network. In humans, functional connectivity between thalamus and ventral striatum correlated with depressive and fatigue-related symptoms. In mice, psoriasis-like inflammation produced impaired thalamostriatal synaptic transmission accompanied by anhedonia and motivation-related behavioural deficits, together with glial activation and immune-cell infiltration. These cross-species findings identify the thalamostriatal circuit as a conserved neuroinflammatory hotspot involved in depression and highlight it as a potential therapeutic target.

neuroscience↗

bioRxiv2021

Hippocampal CA1 pyramidal cells do not receive monosynaptic input from thalamic nucleus reuniens

The prefrontal - hippocampal - entorhinal system is perhaps the most widely-studied circuit in cognitive and systems neuroscience, due to its role in supporting cognitive functions such as working memory and decision-making. Disrupted communication within this circuit is a key feature of disorders such as schizophrenia and dementia. Nucleus reuniens (NRe) is a midline thalamic nucleus that sits at the nexus of this circuit, linking these regions together. As there are no direct projections from prefrontal cortex to hippocampus, the accepted model is that the NRe mediates prefrontal drive of hippocampal activity, although these connections are poorly defined at the cellular and synaptic level. Using ex vivo optogenetics and electrophysiology, alongside monosynaptic circuit-tracing, we sought to test the mechanisms through which NRe could drive hippocampal activity. Unexpectedly, we found no evidence that pyramidal cells in CA1 receive input from NRe, with midline thalamic input to hippocampus proper appearing selective for GABAergic interneurons. In other regions targeted by NRe, we found that pyramidal cells in prosubiculum and subiculum received synaptic inputs from NRe that were at least an order of magnitude weaker than those in prefrontal or entorhinal cortices. We conclude that, contrary to widely-held assumptions in the field, the hippocampal pyramidal cells are not a major target of nucleus reuniens.

neuroscience↗

bioRxiv2021

Chemogenetic activation of midline thalamic nuclei fails to ameliorate memory deficits in two mouse models of Alzheimer's disease

One of the main features of Alzheimers disease is the progressive loss of memory, likely due to pathological changes within brain regions such as the hippocampus and entorhinal cortex. These structures are embedded within the extended memory circuit, an interconnected set of brain regions that are essential for episodic memory. The anterior thalamic nuclei (ATN) and thalamic nucleus reuniens (NRe) are both extensively and reciprocally connected with these important memory regions, so we sought to test the hypothesis that chemogenetically-enhancing neurotransmission through NRe and ATN would ameliorate memory deficits in two mechanistically-distinct mouse models of Alzheimers disease. Using the hAPP-J20 mouse model of amyloidopathy and the Tg4510 mouse model of tauopathy, we carried out stereotaxic injections of viral vectors to transduce hM3Dq (Gq)_mCherry into NRe or the anterio-dorsal/anterio-ventral nuclei of ATN, using mCherry as a control. At nine months (hAPP-J20) or six months (Tg4510) of age, mice underwent a behaviour battery of open field (OF), novel object recognition (NOR) and radial arm maze (RAM), with DREADD agonist 21 administered 30min prior to each behaviour test. Tissue was collected post-behaviour to confirm injection site and virus expression. Both Tg4510 and hAPP-J20 mice show marked hyperactivity in the OF, significant deficits in recognition memory, and a significant impairment in spatial reference and spatial working memory. Unexpectedly, chemogenetic activation of ATN or NRe did not significantly improve spatial memory impairments or reduce the observed hyperactivity, although NRe activation did modestly rescue recognition memory in J20 mice. This may be due to compensation elsewhere within the memory circuit, or that the pathological changes are too far advanced for behaviour reversal.

neuroscience↗