CCR5 closes the temporal window for memory linking.

Real-world memories are formed in a particular context and are often not acquired or recalled in isolation1-5. Time is a key variable in the organization of memories, as events that are experienced close in time are more likely to be meaningfully associated, whereas those that are experienced with a longer interval are not1-4. How the brain segregates events that are temporally distinct is unclear. Here we show that a delayed (12-24 h) increase in the expression of C-C chemokine receptor type 5 (CCR5)-an immune receptor that is well known as a co-receptor for HIV infection6,7-after the formation of a contextual memory determines the duration of the temporal window for associating or linking that memory with subsequent memories. This delayed expression of CCR5 in mouse dorsal CA1 neurons results in a decrease in neuronal excitability, which in turn negatively regulates neuronal memory allocation, thus reducing the overlap between dorsal CA1 memory ensembles. Lowering this overlap affects the ability of one memory to trigger the recall of the other, and therefore closes the temporal window for memory linking. Our findings also show that an age-related increase in the neuronal expression of CCR5 and its ligand CCL5 leads to impairments in memory linking in aged mice, which could be reversed with a Ccr5 knockout and a drug approved by the US Food and Drug Administration (FDA) that inhibits this receptor, a result with clinical implications. Altogether, the findings reported here provide insights into the molecular and cellular mechanisms that shape the temporal window for memory linking.

Alzheimer risk-increasing TREM2 variant causes aberrant cortical synapse density and promotes network hyperexcitability in mouse models.

The R47H variant of triggering receptor expressed on myeloid cells 2 (TREM2) increases the risk of Alzheimer's disease (AD). To investigate potential mechanisms, we analyzed knockin mice expressing human TREM2-R47H from one mutant mouse Trem2 allele. TREM2-R47H mice showed increased seizure activity in response to an acute excitotoxin challenge, compared to wildtype controls or knockin mice expressing the common variant of human TREM2. TREM2-R47H also increased spontaneous thalamocortical epileptiform activity in App knockin mice expressing amyloid precursor proteins bearing autosomal dominant AD mutations and a humanized amyloid-ß sequence. In mice with or without such App modifications, TREM2-R47H increased the density of putative synapses in cortical regions without amyloid plaques. TREM2-R47H did not affect synaptic density in hippocampal regions with or without plaques. We conclude that TREM2-R47H increases AD-related network hyperexcitability and that it may do so, at least in part, by causing an imbalance in synaptic densities across brain regions.

Insight into the roles of CCR5 in learning and memory in normal and disordered states.

As cognitive impairments continue to rise in prevalence, there is an urgent need to understand the mechanisms of learning and memory in normal and disordered states. C-C chemokine receptor 5 (CCR5) has been implicated in the regulation of multiple forms of learning and memory via its regulation on learning-related cell signaling and neuronal plasticity. As a chemokine receptor and a co-receptor for HIV, CCR5's role in immune response and HIV-associated neurocognitive disorder (HAND) has been widely studied. In contrast, CCR5 is less understood in cognitive deficits associated with other disorders, including Alzheimer's disease (AD), stroke and certain psychiatric disorders. A broad overview of the present literature shows that CCR5 acts as a potent suppressor of synaptic plasticity and learning and memory, although a few studies have reported the opposite effect of CCR5 in stroke or AD animal models. By summarizing the current literature of CCR5 in animal and human studies of cognition, this review aims to provide a comprehensive overview of the role of CCR5 in learning and memory in both normal and disordered states and to discuss the possibility of CCR5 suppression as an effective therapeutic to alleviate cognitive deficits in HAND, AD, and stroke.

Secondary thalamic neuroinflammation after focal cortical stroke and traumatic injury mirrors corticothalamic functional connectivity.

While cortical injuries, such as traumatic brain injury (TBI) and neocortical stroke, acutely disrupt the neocortex, most of their consequent disabilities reflect secondary injuries that develop over time. Thalamic neuroinflammation has been proposed to be a biomarker of cortical injury and of the long-term cognitive and neurological deficits that follow. However, the extent to which thalamic neuroinflammation depends on the type of cortical injury or its location remains unknown. Using two mouse models of focal neocortical injury that do not directly damage subcortical structures-controlled cortical impact and photothrombotic ischemic stroke-we found that chronic neuroinflammation in the thalamic region mirrors the functional connections with the injured cortex, and that sensory corticothalamic regions may be more likely to sustain long-term damage than nonsensory circuits. Currently, heterogeneous clinical outcomes complicate treatment. Understanding how thalamic inflammation depends on the injury site can aid in predicting features of subsequent deficits and lead to more effective, customized therapies.