Biology subjects

Andrianova, L.

Publications and source records attributed to Andrianova, L..

8 recordsLinked to original sources

bioRxiv2025

Anterior thalamic nucleus inputs to the retrosplenial cortex are unperturbed in the hAPP-J20 mouse model of Alzheimer's disease

Alzheimers disease (AD) is a neurodegenerative condition characterised by progressive loss of memory and general decline in cognitive function. Although research has traditionally focused on the hippocampus and entorhinal cortex, other regions important for memory and spatial navigation, such as the anterior thalamic nuclei (ATN) and retrosplenial cortex (RSC), are also affected. The RSC is an important brain region for both memory and spatial navigation, and displays dysfunction in humans during prodromal phases of AD. The ATN provide a major input to RSC, with loss of this input to RSC causing a dramatic reduction in the expression of the immediate early gene product c-Fos. The ATN to RSC connection may thus present a new target for therapeutic intervention in AD. Here, we set out to determine whether AD-like pathology perturbed projections from ATN to RSC using the hAPP-J20 amyloidopathy mouse model, using optogenetic activation of thalamic inputs combined with ex vivo patch clamp electrophysiology. We found that RSC displayed an age-dependent decline in basal c-Fos activity, with no additional effect of amyloid pathology on c-Fos expression. At all time points (3, 6 and 9 months) measured, we found no evidence of impairments in the synaptic strength or efficacy of the ATN projections to either granular or dysgranular subdivisions of RSC. We conclude that, in the hAPP-J20 mouse model, this pathway is unaffected by amyloid-{beta} overexpression.

neuroscience↗

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↗

bioRxiv2025

Dissection of retrosplenial cortex inputs: ubiquitous drive from anterior thalamus

The retrosplenial cortex (RSC) is a highly interconnected brain region involved in spatial navigation and associative learning. It forms extensive, reciprocal connections with sensory, hippocampal, parahippocampal, prefrontal, and thalamic areas. RSC comprises granular (gRSC) and dysgranular (dRSC) subdivisions with distinct connectivity and functions. Despite its emerging role in behaviour and its implication in memory-related disorders such as Alzheimers disease, the nature of its synaptic inputs remains poorly understood. Here, we combined viral anatomical tracing, optogenetic stimulation, and patch-clamp electrophysiology to investigate inputs from the anterior cingulate cortex (ACC), dorsal subiculum (dSub), and anterior thalamic nuclei (ATN) to gRSC and dRSC. Strikingly, all recorded RSC pyramidal neurons received ATN input, regardless of subdivision or cortical layer. Activation of ATN inputs evoked significantly larger post-synaptic responses than those from dSub or ACC, though both regions maintained substantial connectivity with RSC. While dSub projections appeared denser in gRSC, synaptic responses were larger in dRSC, albeit with lower input probability. Notably, NMDA receptor-mediated components of RSC excitatory inputs were weaker than expected, potentially explaining the reported inability to induce long-term potentiation in RSC in ex vivo neurophysiology experiments. This is the first study to characterise the synaptic properties of retrosplenial afferents. Our findings highlight the dominant influence of ATN inputs and raise important questions about how RSCs long-range connectivity supports its roles in memory and spatial navigation.

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↗

bioRxiv2022

Alterations to parvalbumin-expressing interneuron function and associated network oscillations in the hippocampal - medial prefrontal cortex circuit during natural sleep in APPNL-G-F mice

In the early stages of Alzheimers disease (AD), the accumulation of the peptide amyloid-{beta} (A{beta}) damages synapses and disrupts neuronal activity and leads to disruption of neuronal oscillations associated with cognition. This is thought to be largely due to impairments in CNS synaptic inhibition, particularly via parvalbumin (PV)-expressing interneurons that essential for generating several key oscillations. Research in this field has largely been conducted in mouse models that over-express humanised, mutated forms of AD-associated genes that produce exaggerated pathology. This has prompted the development and use of knock-in mouse lines that express these genes at an endogenous level, such as the AppNL-G-F/NL-G-F mouse model used in the present study. These mice appear to model the early stages of A{beta}-induced network impairments, yet an in-depth characterisation of these impairments in currently lacking. Therefore, using 16 month-old AppNL-G-F/NL-G-F mice, we analysed neuronal oscillations found in the hippocampal - medial prefrontal cortex (mPFC) during awake behaviour, rapid eye movement (REM) and non-REM (NREM) sleep to assess the extent of network dysfunction. No alterations to gamma oscillations were found to occur in the hippocampus or mPFC during either awake behaviour, REM or NREM sleep. However, during NREM sleep an increase in the amplitude of mPFC spindles and decrease in the power of hippocampal SWRs was identified. The former was associated with a decrease in the density of mPFC PV-expressing interneurons and the latter was accompanied by an increase in the synchronisation of PV-expressing interneuron activity, as measured using two-photon Ca2+ imaging. Furthermore, although changes were detected in local network function of mPFC and hippocampus, long-range communication between these regions appeared intact. Altogether, our results suggest that these NREM sleep-specific impairments represent the early stages of circuit breakdown in response to amyloidopathy.

neuroscience↗

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↗