Biology subjects

Margetts-Smith, G.

Publications and source records attributed to Margetts-Smith, G..

3 recordsLinked to original sources

bioRxiv2022

No evidence from complementary data sources of a direct projection from the mouse anterior cingulate area to the hippocampal formation

The connectivity and interplay between the prefrontal cortex and hippocampus underpin a number of key cognitive processes, with changes in these interactions being implicated in both neurodevelopmental as well as neurodegenerative conditions. Understanding the precise cellular connections through which this circuit is organised is, therefore, vital for understanding these same processes. Overturning earlier findings, a recent study described a novel excitatory projection from anterior cingulate cortex to hippocampus. We sought to validate this unexpected finding using multiple, complementary methods: anterograde and retrograde anatomical tracing, using both anterograde and retrograde AAVs and monosynaptic rabies tracing. Additionally, an extensive data search of the Allen Projection Brain Atlas database was conducted to find the stated projection within any of the deposited anatomical studies, as an independent verification of our own results. However, we failed to find any evidence of a direct, monosynaptic projection from mouse anterior cingulate cortex to the hippocampus proper.

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↗