Human hippocampal circuit characterization
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Latent circuit inference from heterogeneous neural responses during cognitive tasks
Higher cortical areas carry a wide range of sensory, cognitive and motor signals mixed in heterogeneous responses of single neurons tuned to multiple task variables. Dimensionality reduction methods that rely on correlations between neural activity and task variables leave unknown how heterogeneous responses arise from connectivity to drive behavior. We develop the latent circuit model, a dimensionality reduction approach in which task variables interact via low-dimensional recurrent connectivity to produce behavioral output. We apply the latent circuit inference to recurrent neural networks trained to perform a context-dependent decision-making task and find a suppression mechanism in which contextual representations inhibit irrelevant sensory responses. We validate this mechanism by confirming the behavioral effects of patterned connectivity perturbations predicted by the latent circuit model. We find similar suppression of irrelevant sensory responses in the prefrontal cortex of monkeys performing the same task. We show that incorporating causal interactions among task variables is critical for identifying behaviorally relevant computations from neural response data.
Constructing future behavior in the hippocampal formation through composition and replay
The hippocampus is critical for memory, imagination and constructive reasoning. Recent models have suggested that its neuronal responses can be well explained by state spaces that model the transitions between experiences. Here we use simulations and hippocampal recordings to reconcile these views. We show that if state spaces are constructed compositionally from existing building blocks, or primitives, hippocampal responses can be interpreted as compositional memories, binding these primitives together. Critically, this enables agents to behave optimally in new environments with no new learning, inferring behavior directly from the composition. We predict a role for hippocampal replay in building and consolidating these compositional memories. We test these predictions in two datasets by showing that replay events from newly discovered landmarks induce and strengthen new remote firing fields. When the landmark is moved, replay builds a new firing field at the same vector to the new location. Together, these findings provide a framework for reasoning about compositional memories and demonstrate that such memories are formed in hippocampal replay.
A primary cilia–autophagy axis in hippocampal neurons is essential to maintain cognitive resilience
Blood-borne factors are essential to maintain neuronal synaptic plasticity and cognitive resilience throughout life. One such factor is osteocalcin (OCN), a hormone produced by osteoblasts that influences multiple physiological processes, including hippocampal neuronal homeostasis. However, the mechanism through which this blood-borne factor communicates with neurons remains unclear. Here we show the importance of a core primary cilium (PC) protein–autophagy axis in mediating the effects of OCN. We found that the OCN receptor GPR158 is present at the PC of hippocampal neurons and mediates the regulation of autophagy machinery by OCN. During aging, autophagy and PC core proteins are reduced in neurons, and restoring their levels is sufficient to improve cognitive impairments in aged mice. Mechanistically, the induction of this axis by OCN is dependent on the PC-dependent cAMP response element-binding protein signaling pathway. Altogether, this study demonstrates that the PC–autophagy axis is a gateway to mediate communication between blood-borne factors and neurons, and it advances understanding of the mechanisms involved in age-related cognitive decline.
Simultaneous tACS-fMRI reveals state- and frequency-specific modulation of hippocampal-cortical functional connectivity
Non-invasive indirect hippocampal-targeted stimulation is of broad scientific and clinical interest. Transcranial alternating current stimulation (tACS) is appealing because it allows oscillatory stimulation to study hippocampal theta (3–8 Hz) activity. We found that tACS administered during functional magnetic resonance imaging yielded a frequency-, mental state- and topologically-specific effect of theta stimulation (but not other frequencies) enhancing right (but not left) hippocampal-cortical connectivity during resting blocks but not during task blocks. Control analyses showed that this effect was not due to possible stimulation-induced changes in signal quality or head movement. Our findings are promising for targeted network modulations of deep brain structures for research and clinical intervention.
LCN2 induces neuronal loss and facilitates sepsis-associated cognitive impairments
Sepsis-associated encephalopathy (SAE) is a severe neurological syndrome marked by widespread brain dysfunctions due to sepsis. Despite increasing data supporting the hypothesis of neuronal damage, the exact mechanism of sepsis-related cognitive disorders and therapeutic strategies remain unclear and need further investigation. In this study, a sepsis model was established in C57 mice using lipopolysaccharide (LPS). The findings demonstrated that LPS exposure induced neuronal loss, synaptic and cognitive deficits accompanied by mitochondrial damage. Bioinformatics and western blot analyses demonstrated a significant increase in Lipocalin-2 (LCN2) during sepsis as a key hub gene involved in immune and neurological inflammation. Interestingly, the recombinant LCN2 protein exhibited similar effects on synaptic dysfunction and cognitive deficits in C57 mice. Conversely, downregulating LCN2 effectively nullified the impact of LPS, leading to the amelioration of synaptic and cognitive deficits, neuronal loss, and reactive oxygen species (ROS)-associated mitochondrial damage. These findings suggest a novel etiopathogenic mechanism of SAE, which is initiated by the increased LCN2, leading to neuronal loss and cognitive deficit. Inhibition of LCN2 could be therapeutically beneficial in treating sepsis-induced synaptic and cognitive impairments.
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