Aneurysmal subarachnoid hemorrhage (SAH) is a devastating disease that leads to poor neurological outcomes and is characterized by both vascular and neural pathologies. Recent evidence demonstrates that inflammation mediates many of the vascular and neural changes observed after SAH. Although most studies focus on inflammatory mediators such as cytokines, the ultimate effectors of inflammation in SAH are parenchymal brain and peripheral immune cells. As such, the present review will summarize our current understanding of the cellular changes of both CNS parenchymal and peripheral immune cells after SAH.

Background and Purpose: Aneurysmal subarachnoid hemorrhage (SAH) is associated with the development of delayed cognitive deficits. Neutrophil infiltration into the central nervous system is linked to the development of these deficits after SAH. It is however unclear how neutrophil activity influences central nervous system function in SAH. The present project aims to elucidate which neutrophil factors mediate central nervous system injury and cognitive deficits after SAH. Methods: Using a murine model of SAH and mice deficient in neutrophil effector functions, we determined which neutrophil effector function is critical to the development of deficits after SAH. In vivo and in vitro techniques were used to investigate possible pathways of neutrophils effect after SAH. Results: Our results show that mice lacking functional MPO (myeloperoxidase), a neutrophil enzyme, lack both the meningeal neutrophil infiltration (wild type, sham 872 cells/meninges versus SAH 3047, P =0.023; myeloperoxidase knockout [MPOKO], sham 1677 versus SAH 1636, P =NS) and erase the cognitive deficits on Barnes maze associated with SAH (MPOKO sham versus SAH, P =NS). The reintroduction of biologically active MPO, and its substrate hydrogen peroxide (H 2 O 2 ), to the cerebrospinal fluid of MPOKO mice at the time of hemorrhage restores the spatial memory deficit observed after SAH (time to goal box MPOKO sham versus MPOKO+MPO/H 2 O 2 , P =0.001). We find evidence of changes in neurons, astrocytes, and microglia with MPO/H 2 O 2 suggesting the effect of MPO may have complex interactions with many cell types. Neurons exposed to MPO/H 2 O 2 show decreased calcium activity at baseline and after stimulation with potassium chloride. Although astrocytes and microglia are affected, changes seen in astrocytes are most consistent with inflammatory changes that likely affect neurons. Conclusions: These results implicate MPO as a mediator of neuronal dysfunction in SAH through its effect on both neurons and glia. These results show that, in SAH, the activity of innate immune cells in the meninges modulates the activity and function of the underlying brain tissue.

The goals of the present study were to investigate the changes in sympathetic preganglionic neurons following transection of distal axons in the cervical sympathetic trunk (CST) that innervate the superior cervical ganglion (SCG) and to assess changes in the protein expression of brain derived neurotrophic factor (BDNF) and its receptor TrkB in the thoracic spinal cord. . At 1 week, a significant decrease in soma volume and reduced soma expression of choline acetyltransferase (ChAT) in the intermediolateral cell column (IML) of T1 spinal cord were observed, with both ChAT-ir and non-immunoreactive neurons expressing the injury marker activating transcription factor 3. . These changes were transient, and at later time points, ChAT expression and soma volume returned to control values and the number of ATF3 neurons declined. No evidence for cell loss or neuronal apoptosis was detected at any time point. Protein levels of BDNF and/or full length TrkB in the spinal cord were increased throughout the survival period. In the SCG, both ChAT-ir axons and ChAT protein remained decreased at 16 weeks, but were increased compared to the 10 week time point. These results suggest that though IML neurons show reduced ChAT expression and cell volume at 1 week following CST transection, at later time points, the neurons recovered and exhibited no significant signs of neurodegeneration. The alterations in BDNF and/or TrkB may have contributed to the survival of the IML neurons and the recovery of ChAT expression, as well as to the reinnervation of the SCG.

Following peripheral nerve injury, retrograde signals originating from the injury site may activate intrinsic factors in the injured neurons, possibly leading to regenerative growth. Retrograde influences from peripheral injury sites may lead to the activation of glial cells in the vicinity of the centrally located cell bodies of the injured neurons. Few studies have examined changes in the spinal cord intermediolateral cell column (IML), which houses sympathetic preganglionic cell bodies, following injury to distal axons in the cervical sympathetic trunk (CST). The goal of the present study was to determine if transection of the CST results in plasticity in glial cells in the IML. At 1 day following injury, changes in the expression of microglial marker Iba1 were observed and the typical oligodendrocyte-neuronal relationship was altered. By 7 days, astrogliosis, microglial aggregation, and increased numbers of oligodendrocytes, as well as enhanced glial-glial and glial-neuronal relationships were present. The majority of cases were similar to controls at 3 weeks following injury and no changes were observed in any cases at 10 weeks following the injury. These results revealed changes in astrocytes, microglia, oligodendrocytes in the spinal cord following transection of preganglionic axons comprising the CST, indicating their ability to respond to distal axonal injury.

Group I metabotropic glutamate receptors (mGlu1 and 5) have been implicated in synaptic plasticity and learning and memory. However, much of our understanding of how these receptors in different brain regions contribute to distinct memory stages in different learning tasks remains incomplete. The present study investigated the effects of the mGlu5 receptor antagonist, 2-methyl-6-(phenylethynyl)-pyridine (MPEP), and mGlu1 receptor antagonist, (S)-(+)-alpha-amino-4-carboxy-2-methylbenzene-acetic acid (LY 367385) in the dorsal hippocampus on the consolidation and extinction of memory for inhibitory avoidance learning. Male, Sprague-Dawley rats were trained in a single-trial step-down inhibitory avoidance task. MPEP, LY 367385 or saline were infused bilaterally into the CA1 region immediately after training or immediately after the first retention test which was given 24h after training. Rats receiving MPEP (1.5 or 5.0 microg/side) or LY 367385 (0.7 or 2.0 microg/side) infusion exhibited a dose-dependent decrease in retention when tested 24h later. MPEP was ineffective while LY 367385 significantly attenuated extinction when injected after the first retention test using an extinction procedure. These findings indicate a selective participation of hippocampal group I mGlu receptors in memory processing in this task.