Choroid plexus-targeted NKCC1 overexpression to treat post-hemorrhagic hydrocephalus.

Post-hemorrhagic hydrocephalus (PHH) refers to a life-threatening accumulation of cerebrospinal fluid (CSF) that occurs following intraventricular hemorrhage (IVH). An incomplete understanding of this variably progressive condition has hampered the development of new therapies beyond serial neurosurgical interventions. Here, we show a key role for the bidirectional Na-K-Cl cotransporter, NKCC1, in the choroid plexus (ChP) to mitigate PHH. Mimicking IVH with intraventricular blood led to increased CSF [K+] and triggered cytosolic calcium activity in ChP epithelial cells, which was followed by NKCC1 activation. ChP-targeted adeno-associated viral (AAV)-NKCC1 prevented blood-induced ventriculomegaly and led to persistently increased CSF clearance capacity. These data demonstrate that intraventricular blood triggered a trans-choroidal, NKCC1-dependent CSF clearance mechanism. Inactive, phosphodeficient AAV-NKCC1-NT51 failed to mitigate ventriculomegaly. Excessive CSF [K+] fluctuations correlated with permanent shunting outcome in humans following hemorrhagic stroke, suggesting targeted gene therapy as a potential treatment to mitigate intracranial fluid accumulation following hemorrhage.

Inflammation of the Embryonic Choroid Plexus Barrier following Maternal Immune Activation.

The choroid plexus (ChP) regulates brain development by secreting instructive cues and providing a protective brain barrier. Here, we show that polyI:C-mediated maternal immune activation leads to an inflammatory response in the developing embryonic mouse brain that manifests as pro-inflammatory cerebrospinal fluid (CSF) and accumulation of ChP macrophages. Elevation of CSF-CCL2 was sufficient to drive ChP immune cell recruitment, activation, and proliferation. In addition, ChP macrophages abandoned their regular tiling pattern and relocated to the ChP-free margin where they breached the weakened epithelial barrier. We further found that these immune cells entered from the ChP into the brain via anatomically specialized "hotspots" at the distal tips of ChP villi. In vivo two-photon imaging demonstrated that surveillance behaviors in ChP macrophages had already emerged at this early stage of embryogenesis. Thus, the embryonic ChP forms a functional brain barrier that can mount an inflammatory response to external insults.

Cortical reactivations of recent sensory experiences predict bidirectional network changes during learning.

Salient experiences are often relived in the mind. Human neuroimaging studies suggest that such experiences drive activity patterns in visual association cortex that are subsequently reactivated during quiet waking. Nevertheless, the circuit-level consequences of such reactivations remain unclear. Here, we imaged hundreds of neurons in visual association cortex across days as mice learned a visual discrimination task. Distinct patterns of neurons were activated by different visual cues. These same patterns were subsequently reactivated during quiet waking in darkness, with higher reactivation rates during early learning and for food-predicting versus neutral cues. Reactivations involving ensembles of neurons encoding both the food cue and the reward predicted strengthening of next-day functional connectivity of participating neurons, while the converse was observed for reactivations involving ensembles encoding only the food cue. We propose that task-relevant neurons strengthen while task-irrelevant neurons weaken their dialog with the network via participation in distinct flavors of reactivation.

State-specific gating of salient cues by midbrain dopaminergic input to basal amygdala.

Basal amygdala (BA) neurons guide associative learning via acquisition of responses to stimuli that predict salient appetitive or aversive outcomes. We examined the learning- and state-dependent dynamics of BA neurons and ventral tegmental area (VTA) dopamine (DA) axons that innervate BA (VTADA→BA) using two-photon imaging and photometry in behaving mice. BA neurons did not respond to arbitrary visual stimuli, but acquired responses to stimuli that predicted either rewards or punishments. Most VTADA→BA axons were activated by both rewards and punishments, and they acquired responses to cues predicting these outcomes during learning. Responses to cues predicting food rewards in VTADA→BA axons and BA neurons in hungry mice were strongly attenuated following satiation, while responses to cues predicting unavoidable punishments persisted or increased. Therefore, VTADA→BA axons may provide a reinforcement signal of motivational salience that invigorates adaptive behaviors by promoting learned responses to appetitive or aversive cues in distinct, intermingled sets of BA excitatory neurons.