Paraventricular nucleus-central amygdala oxytocinergic projection modulates pain-related anxiety-like behaviors in mice

Aims

Anxiety disorders associated with pain are a common health problem. However, the underlying mechanisms remain poorly understood. We aimed to investigate the role of paraventricular nucleus (PVN)-central nucleus of the amygdala (CeA) oxytocinergic projections in anxiety-like behaviors induced by inflammatory pain.

Methods

After inflammatory pain induction by complete Freund's adjuvant (CFA), mice underwent elevated plus maze, light–dark transition test, and marble burying test to examine the anxiety-like behaviors. Chemogenetic, optogenetic, and fiber photometry recordings were used to modulate and record the activity of the oxytocinergic projections of the PVN-CeA.

Results

The key results are as follows: inflammatory pain-induced anxiety-like behaviors in mice accompanied by decreased activity of PVN oxytocin neurons. Chemogenetic activation of PVN oxytocin neurons prevented pain-related anxiety-like behaviors, whereas inhibition of PVN oxytocin neurons induced anxiety-like behaviors in naïve mice. PVN oxytocin neurons projected directly to the CeA, and microinjection of oxytocin into the CeA blocked anxiety-like behaviors. Inflammatory pain also decreased the activity of CeA neurons, and optogenetic activation of PVN^oxytocin-CeA circuit prevented anxiety-like behavior in response to inflammatory pain.

Conclusion

The results of our study suggest that oxytocin has anti-anxiety effects and provide novel insights into the role of PVN^oxytocin-CeA projections in the regulation of anxiety-like behaviors induced by inflammatory pain.     

Amygdalo-nigral circuit mediates stress-induced vulnerability to the parkinsonian toxin MPTP

Aims

The aim was to investigate the effect of mood disorders on parkinsonian toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced motor disability, substantia nigra pars compacta (SNc) dopaminergic (DA) neurons loss. Also, the neural circuit mechanism was elucidated.

Methods

The depression-like (physical stress, PS) and anxiety-like (emotional stress, ES) mouse models were established by the three-chamber social defeat stress (SDS). The features of Parkinson's disease were reproduced by MPTP injection. Viral-based whole-brain mapping was utilized to resolve the stress-induced global changes in direct inputs onto SNc DA neurons. Calcium imaging and chemogenetic techniques were applied to verify the function of the related neural pathway.

Results

We found that PS mice, but not ES mice, showed worse movement performance and more SNc DA neuronal loss than control mice after MPTP administration. The projection from the central amygdala (CeA) to the SNc^DA was significantly increased in PS mice. The activity of SNc-projected CeA neurons was enhanced in PS mice. Activating or inhibiting the CeA-SNc^DA pathway could mimic or block PS-induced vulnerability to MPTP.

Conclusions

These results indicated that projections from CeA to SNc DA neurons contribute to SDS-induced vulnerability to MPTP in mice.     

Selective ablation of type 3 adenylyl cyclase in somatostatin-positive interneurons produces anxiety- and depression-like behaviors in mice

BACKGROUNDMajor depressive disorder (MDD) is a highly disabling psychiatric syndrome associated with deficits of specific subpopulations of cortical GABAergic interneurons; however, the underlying molecular mechanism remains unknown. Type 3 adenylyl cyclase (ADCY3, AC3), which is important for neuronal excitability, has been implicated in MDD in a genome-wide association study in humans. Moreover, a study reported that ablation of AC3 in mice caused similar symptoms as MDD patients.AIMTo determine if disruption of the AC3 gene in different subtypes of GABAergic interneurons of mice causes depression-like behaviors.METHODSUsing immunohistochemistry, we investigated the expression of AC3 in two major subtypes GABAergic interneurons: Somatostatin-positive (SST⁺) and parvalbumin-positive (PV⁺) neurons. Genetic manipulations were used to selectively disrupt AC3 expression in SST⁺ or PV⁺ interneurons. A series of behavior tests including rotarod test, open field test (OFT), elevated plus maze test (EPM), forced swimming test (FST), and tail suspension test (TST) were used to evaluate the motor ability, anxiety- and depression- like behaviors, respectively.RESULTSOur results indicate that approximately 90.41% of SST⁺ and 91.22% of PV⁺ interneurons express AC3. After ablation of AC3 in SST⁺ interneurons, the mice spent comparable time in the center area in OFT, but significantly less time in the open arms and low frequency of entries to the open arms in EPM. Furthermore, these mice showed prolonged immobility in FST and more freezing in TST. However, there were no significant changes in these behaviors after specific disruption of AC3 in PV⁺ interneurons.CONCLUSIONThis study indicates that ablation of AC3 in SST⁺ interneurons of mice increases anxiety- and depression-like behaviors in mice, supporting the general hypothesis that decreased AC3 activity may play a role in human depression.     

Microglial activation in the dorsal striatum participates in anxiety-like behavior in Cyld knockout mice

CYLD lysine 63 deubiquitinase (CYLD), that is mainly involved in immune responses and inflammation, is expressed at high levels in the brain, especially in the dorsal striatum, but its physiological function of CYLD in the brain remains unexplored. The present study investigated the effect of Cyld gene knockout on behavior relevant to the dorsal striatum, such as motor activity and depression-like and anxiety-like behavior. Microglia and the pro-inflammatory cytokines including interleukin (IL)-1 β and tumor necrosis factor (TNF)- α were evaluated in the dorsal striatum to elucidate the underlying mechanism. Cyld knockout (Cyld^-/-) mice exhibited anxiety-like behavior, but not motor deficits or depression-like behavior. Microglia were activated and the mRNA levels of IL-1 β and TNF- α were increased in the dorsal striatum of Cyld^-/- mice compared to Cyld^+/+ mice. The microglial modulator minocycline partially reversed the anxiety-like behavior, microglial activation and increase in IL-1 β and TNF- α mRNA and protein levels in the dorsal striatum of Cyld^-/- mice. Collectively, these results suggest that Cyld knockout leading to microglial activation promotes IL-1 β and TNF- α expression and acts as a critical pathway in the pathophysiology of anxiety.     

Degeneration of proprioceptive sensory nerve endings in mice harboring amyotrophic lateral sclerosis–causing mutations

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that primarily targets the motor system. Although much is known about the effects of ALS on motor neurons and glial cells, little is known about its effect on proprioceptive sensory neurons. This study examines proprioceptive sensory neurons in mice harboring mutations associated with ALS, in SOD1^G93A and TDP43^A315T transgenic mice. In both transgenic lines, we found fewer proprioceptive sensory neurons containing fluorescently tagged cholera toxin in their soma five days after injecting this retrograde tracer into the tibialis anterior muscle. We asked whether this is due to neuronal loss or selective degeneration of peripheral nerve endings. We found no difference in the total number and size of proprioceptive sensory neuron soma between symptomatic SOD1^G93A and control mice. However, analysis of proprioceptive nerve endings in muscles revealed early and significant alterations at Ia/II proprioceptive nerve endings in muscle spindles before the symptomatic phase of the disease. Although these changes occur alongside those at α‐motor axons in SOD1^G93A mice, Ia/II sensory nerve endings degenerate in the absence of obvious alterations in α‐motor axons in TDP43^A315T transgenic mice. We next asked whether proprioceptive nerve endings are similarly affected in the spinal cord and found that nerve endings terminating on α‐motor neurons are affected during the symptomatic phase and after peripheral nerve endings begin to degenerate. Overall, we show that Ia/II proprioceptive sensory neurons are affected by ALS‐causing mutations, with pathological changes starting at their peripheral nerve endings. J. Comp. Neurol. 523:2477–2494, 2015. © 2015 Wiley Periodicals, Inc.     

Protein tyrosine phosphatase receptor type O regulates development and function of the sensory nervous system

The roles of protein tyrosine phosphatases (PTPs) in differentiation and axon targeting by dorsal root ganglion (DRG) neurons are essentially unknown. The type III transmembrane PTP, PTPRO, is expressed in DRG neurons, and is implicated in the guidance of motor and retinal axons. We examined the role of PTPRO in DRG development and function using PTPRO^−/− mice. The number of peptidergic nociceptive neurons in the DRG of PTPRO^−/− mice was significantly decreased, while the total number of sensory neurons appeared unchanged. In addition, spinal pathfinding by both peptidergic and proprioceptive neurons was abnormal in PTPRO^−/− mice. Lastly, PTPRO^−/− mice performed abnormally on tests of thermal pain and sensorimotor coordination, suggesting that both nociception and proprioception were perturbed. Our data indicate that PTPRO is required for peptidergic differentiation and process outgrowth of sensory neurons, as well as mature sensory function, and provide the first evidence that RPTPs regulate DRG development.     

Neonatal blockade of GABA-A receptors alters behavioral and physiological phenotypes in adult mice

Gamma-aminobutyric acid (GABA) plays an inhibitory role in the mature brain, and has a complex and bidirectional effect in different parts of the immature brain which affects proliferation, migration and differentiation of neurons during development. There is also increasing evidence suggesting that activation or blockade of the GABA-A receptors during early life can induce brain and behavioral abnormalities in adulthood. We investigated whether neonatal blockade of the GABA-A receptors by bicuculline can alter anxiety- and depression-like behaviors, body weight, food intake, corticosterone and testosterone levels in adult mice (postnatal days 80–95). To this end, neonatal mice were treated with either DMSO or bicuculline (70, 150 and 300 μg/kg) during postnatal days 7, 9 and 11. When grown to adulthood, mice were exposed to behavioral tests to measure anxiety- (elevated plus-maze and light-dark box) and depression-like behaviors (tail suspension test and forced swim test). Stress-induced serum corticosterone and testosterone levels, body weight and food intake were also evaluated. Neonatal bicuculline exposure at dose of 300 μg/kg decreased anxiety-like behavior, stress-induced corticosterone levels and increased testosterone levels, body weight and food intake, without significantly influencing depression-like behavior in adult male mice. However, no significant changes in these parameters were observed in adult females. These findings suggest that neonatal blockade of GABA-A receptors affects anxiety-like behavior, physiological and hormonal parameters in a sex-dependent manner in mice. Taken together, these data corroborate the concept that GABA-A receptors during early life have an important role in programming neurobehavioral phenotypes in adulthood.     

Combined ampakine and BDNF treatments enhance poststroke functional recovery in aged mice via AKT-CREB signaling

Cerebral ischemia results in damage to neuronal circuits and lasting impairment in function. We have previously reported that stimulation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors with the ampakine, CX1837, increases brain-derived neurotrophic factor (BDNF) levels and affords significant motor recovery after stroke in young mice. Here, we investigated whether administration of CX1837 in aged (24 months old) mice was equally effective. In a model of focal ischemia, administration of CX1837 from 5 days after stroke resulted in a small gain of motor function by week 6 after stroke. Mice that received a local delivery of BDNF via hydrogel implanted into the stroke cavity also showed a small gain of function from 4 to 6 weeks after stroke. Combining both treatments, however, resulted in a marked improvement in motor function from 2 weeks after insult. Assessment of peri-infarct tissue 2 weeks after stroke revealed a significant increase in p-AKT and p-CREB after the combined drug treatment. Using the pan-AKT inhibitor, GSK-690693, or deletion of CREB from forebrain neurons using the CREB-flox/CAMKii-cre mice, we were able to block the recovery of motor function. These data suggest that combined CX1837 and local delivery of BDNF are required to achieve maximal functional recovery after stroke in aged mice, and is occurring via the AKT-GSK3-CREB signaling pathway.     

The Gliopeptide ODN,a Ligand for the Benzodiazepine Site of GABAA Receptors,Boosts Functional Recovery after Stroke

Following stroke, the survival of neurons and their ability to reestablish connections is critical to functional recovery. This is strongly influenced by the balance between neuronal excitation and inhibition. In the acute phase of experimental stroke, lethal hyperexcitability can be attenuated by positive allosteric modulation of GABA_A receptors (GABA_ARs). Conversely, in the late phase, negative allosteric modulation of GABA_AR can correct the suboptimal excitability and improves both sensory and motor recovery. Here, we hypothesized that octadecaneuropeptide (ODN), an endogenous allosteric modulator of the GABA_AR synthesized by astrocytes, influences the outcome of ischemic brain tissue and subsequent functional recovery. We show that ODN boosts the excitability of cortical neurons, which makes it deleterious in the acute phase of stroke. However, if delivered after day 3, ODN is safe and improves motor recovery over the following month in two different paradigms of experimental stroke in mice. Furthermore, we bring evidence that, during the subacute period after stroke, the repairing cortex can be treated with ODN by means of a single hydrogel deposit into the stroke cavity.SIGNIFICANCE STATEMENT Stroke remains a devastating clinical challenge because there is no efficient therapy to either minimize neuronal death with neuroprotective drugs or to enhance spontaneous recovery with neurorepair drugs. Around the brain damage, the peri-infarct cortex can be viewed as a reservoir of plasticity. However, the potential of wiring new circuits in these areas is restrained by a chronic excess of GABAergic inhibition. Here we show that an astrocyte-derived peptide, can be used as a delayed treatment, to safely correct cortical excitability and facilitate sensorimotor recovery after stroke.     

Seizure-induced activation of the HPA axis increases seizure frequency and comorbid depression-like behaviors

Our laboratory recently demonstrated that seizures activate the hypothalamic-pituitary-adrenal (HPA) axis, increasing circulating levels of corticosterone (O'Toole et al., 2013). Given the well-established proconvulsant actions of corticosterone, we hypothesized that seizure-induced activation of the HPA axis may contribute to future seizure susceptibility. Further, since hypercortisolism is associated with depression, we propose that seizure-induced activation of the HPA axis may contribute to comorbid depression and epilepsy. To test this hypothesis, we generated mice lacking the GABAA receptor (GABAAR) δ subunit specifically in corticotropin-releasing hormone (CRH) neurons (Gabrd/Crh mice), which exhibit hyporeactivity of the HPA axis (Lee et al., 2014). Gabrd/Crh mice exhibit blunted seizure-induced elevations in corticosterone, establishing a useful tool to investigate the contribution of HPA axis dysfunction on epilepsy and associated comorbidities. Interestingly, Gabrd/Crh mice exhibit decreased acute seizure susceptibility following kainic acid (KA) administration. Furthermore, chronically epileptic Gabrd/Crh mice exhibit a decrease in both spontaneous seizure frequency and depression-like behaviors compared with chronically epileptic Cre^−/− littermates. Seizure susceptibility and associated depression-like behaviors can be restored to wild type levels by treating Gabrd/Crh mice with exogenous corticosterone. Similarly, chemogenetic activation of CRH neurons in the paraventricular nucleus (PVN) is sufficient to increase seizure susceptibility; whereas, chemogenetic inhibition of CRH neurons in the PVN of the hypothalamus is sufficient to decrease seizure susceptibility and depression-like behaviors in chronically epileptic mice. These data suggest that seizure-induced activation of the HPA axis promotes seizure susceptibility and comorbid depression-like behaviors, suggesting that the HPA axis may be a novel target for seizure control.     

Chronic exposure to cannabinoids during adolescence but not during adulthood impairs emotional behaviour and monoaminergic neurotransmission

The pathophysiological neural mechanism underlying the depressogenic and anxiogenic effects of chronic adolescent cannabinoid use may be linked to perturbations in monoaminergic neurotransmission. We tested this hypothesis by administering the CB₁ receptor agonist WIN55,212-2, once daily for 20 days to adolescent and adult rats, subsequently subjecting them to tests for emotional reactivity paralleled by the in vivo extracellular recordings of serotonergic and noradrenergic neurons. Chronic adolescent exposure but not adult exposure to low (0.2 mg/kg) and high (1.0 mg/kg) doses led to depression-like behaviour in the forced swim and sucrose preference test, while the high dose also induced anxiety-like consequences in the novelty-suppressed feeding test. Electrophysiological recordings revealed both doses to have attenuated serotonergic activity, while the high dose also led to a hyperactivity of noradrenergic neurons only after adolescent exposure. These suggest that long-term exposure to cannabinoids during adolescence induces anxiety-like and depression-like behaviours in adulthood and that this may be instigated by serotonergic hypoactivity and noradrenergic hyperactivity.     

Strain-dependent effects of prenatal maternal immune activation on anxiety- and depression-like behaviors in offspring

There is converging evidence that prenatal maternal infection can increase the risk of occurrence of neuropsychiatric disorders like schizophrenia, autism, anxiety and depression in later life. Experimental studies have shown conflicting effects of prenatal maternal immune activation on anxiety-like behavior and hypothalamic–pituitary–adrenal (HPA) axis development in offspring. We investigated the effects of maternal immune activation during pregnancy on anxiety- and depression-like behaviors in pregnant mice and their offspring to determine whether these effects are dependent on strain. NMRI and C57BL/6 pregnant mice were treated with either saline or lipopolysaccharide on gestational day 17 and then interleukin (IL)-6 and corticosterone (COR) levels; anxiety or depression in the pregnant mice and their offspring were evaluated. The results indicate that maternal inflammation increased the levels of COR and anxiety-like behavior in NMRI pregnant mice, but not in C57BL/6 dams. Our data also demonstrate that maternal inflammation elevated the levels of anxiety-and depression-like behaviors in NMRI offspring on the elevated plus-maze, elevated zero-maze, tail suspension test and forced swimming test respectively, but not in the open field and light–dark box. In addition, we did not find any significant change in anxiety- and depression-like behaviors of adult C57BL/6 offspring. Our findings suggest that prenatal maternal immune activation can alter the HPA axis activity, anxiety- and depression-like behaviors in a strain- and task-dependent manner in offspring and further comprehensive studies are needed to prove the causal relationship between the findings found here and to validate their relevance to neuropsychiatric disorders in humans.     

Beneficial effects of gfap/vimentin reactive astrocytes for axonal remodeling and motor behavioral recovery in mice after stroke

The functional role of reactive astrocytes after stroke is controversial. To elucidate whether reactive astrocytes contribute to neurological recovery, we compared behavioral outcome, axonal remodeling of the corticospinal tract (CST), and the spatio‐temporal change of chondroitin sulfate proteoglycan (CSPG) expression between wild‐type (WT) and glial fibrillary acidic protein/vimentin double knockout (GFAP^–/–Vim^–/–) mice subjected to Rose Bengal induced cerebral cortical photothrombotic stroke in the right forelimb motor area. A foot‐fault test and a single pellet reaching test were performed prior to and on day 3 after stroke, and weekly thereafter to monitor functional deficit and recovery. Biotinylated dextran amine (BDA) was injected into the left motor cortex to anterogradely label the CST axons. Compared with WT mice, the motor functional recovery and BDA‐positive CST axonal length in the denervated side of the cervical gray matter were significantly reduced in GFAP^–/–Vim^–/– mice (n = 10/group, P < 0.01). Immunohistological data showed that in GFAP^–/–Vim^–/– mice, in which astrocytic reactivity is attenuated, CSPG expression was significantly increased in the lesion remote areas in both hemispheres, but decreased in the ischemic lesion boundary zone, compared with WT mice (n = 12/group, P < 0.001). Our data suggest that attenuated astrocytic reactivity impairs or delays neurological recovery by reducing CST axonal remodeling in the denervated spinal cord. Thus, manipulation of astrocytic reactivity post stroke may represent a therapeutic target for neurorestorative strategies. GLIA 2014;62:2022–2033     

Functional testing in a mouse stroke model induced by occlusion of the distal middle cerebral artery

Reducing post-stroke disability is the major goal of stroke therapy. Consequently, functional testing is essential in experimental stroke studies to increase the predictive value of animal models. We used several sensory and motor tests to assess functional disability in a mouse model of permanent distal middle cerebral artery occlusion (pdMCAO) that induced mainly cortical infarcts. Gait dynamics were transiently disturbed after pdMCAO as measured by different analysis techniques. Stance and brake duration were shorter after pdMCAO. Consistent with sensory and motor deficits the latency to move was prolonged up to 14 days after pdMCAO and the performance in the corner test and handedness were affected on day 1 or 2 after pdMCAO. Heart rate was decreased and heart rate variability were increased after pdMCAO indicating sympathetic–parasympathetic imbalance. In summary, pdMCAO-induced cortical infarcts lead to clinically relevant sensory, motor and cardiac autonomic dysfunction in mice. The present study provides a basis to explore the potential of functional testing for neuroprotection and neuroregeneration after stroke.     

Transcutaneous Auricular Vagus Nerve Stimulation with Upper Limb Repetitive Task Practice May Improve Sensory Recovery in Chronic Stroke

Background: Sensory impairment is associated with reduced functional recovery in stroke survivors. Invasive vagus nerve stimulation (VNS) paired with rehabilitative interventions improves motor recovery in chronic stroke. Noninvasive approaches, for example, transcutaneous auricular VNS (taVNS) are safe, well-tolerated and may also improve motor function in those with residual weakness. We report the impact of taVNS paired with a motor intervention, repetitive task practice, on sensory recovery in a cohort of patients with chronic stroke. Methods: Twelve participants who were more than 3 months postischemic stroke with residual upper limb weakness received 18 × 1 hour sessions over 6 weeks with an average of at least 300 repetitions of functional arm movements per session concurrently with taVNS at maximum tolerated intensity. Light touch and proprioception were scored as part of the Upper Limb Fugl-Meyer (UFM) assessment at baseline and postintervention (score range for sensation 0-12). Results: Eleven participants (92%) had sensory impairment at baseline of whom 7 (64%) regained some sensation (proprioception n = 6 participants, light touch n = 2, both modalities n = 1) postintervention. The maximal increase in UFM sensation score (3 points) was seen in the patient with the greatest improvement in motor function. Conclusions: taVNS paired with motor rehabilitation may improve sensory recovery in chronic stroke patients. The relative contribution of motor and sensory rehabilitation to overall functional recovery in chronic stroke needs further characterization in a larger, phase 2 study.     

Intrastriatal transplantation of bone marrow nonhematopoietic cells improves functional recovery after stroke in adult mice.

The authors transplanted adult bone marrow nonhematopoietic cells into the striatum after embolic middle cerebral artery occlusion (MCAO). Mice (n = 23; C57BL/6J) were divided into four groups: (1) mice (n = 5) were subjected to MCAO and transplanted with bone marrow nonhematopoietic cells (prelabeled by bromodeoxyuridine, BrdU) into the ischemic striatum, (2) MCAO alone (n = 8), (3) MCAO with injection of phosphate buffered saline (n = 5), and (4) bone marrow nonhematopoietic cells injected into the normal striatum (n = 5). Mice were killed at 28 days after stroke. BrdU reactive cells survived and migrated a distance of approximately 2.2 mm from the grafting areas toward the ischemic areas. BrdU reactive cells expressed the neuronal specific protein NeuN in 1% of BrdU stained cells and the astrocytic specific protein glial fibrillary acidic protein (GFAP) in 8% of the BrdU stained cells. Functional recovery from a rotarod test (P < 0.05) and modified neurologic severity score tests (including motor, sensory, and reflex; P < 0.05) were significantly improved in the mice receiving bone marrow nonhematopoietic cells compared with MCAO alone. The current findings suggest that the intrastriatal transplanted bone marrow nonhematopoietic cells survived in the ischemic brain and improved functional recovery of adult mice even though infarct volumes did not change significantly. Bone marrow nonhematopoietic cells may provide a new avenue to promote recovery of injured brain.     

Acetylated α-tubulin alleviates injury to the dendritic spines after ischemic stroke in mice

Background and Aim

Functional recovery is associated with the preservation of dendritic spines in the penumbra area after stroke. Previous studies found that polymerized microtubules (MTs) serve a crucial role in regulating dendritic spine formation and plasticity. However, the mechanisms that are involved are poorly understood. This study is designed to understand whether the upregulation of acetylated α-tubulin (α-Ac-Tub, a marker for stable, and polymerized MTs) could alleviate injury to the dendritic spines in the penumbra area and motor dysfunction after ischemic stroke.

Methods

Ischemic stroke was mimicked both in an in vivo and in vitro setup using middle cerebral artery occlusion and oxygen–glucose deprivation models. Thy1-YFP mice were utilized to observe the morphology of the dendritic spines in the penumbra area. MEC17 is the specific acetyltransferase of α-tubulin. Thy1 Cre^ERT2-eYFP and MEC17^fl/fl mice were mated to produce mice with decreased expression of α-Ac-Tub in dendritic spines of pyramidal neurons in the cerebral cortex. Moreover, AAV-PHP.B-DIO-MEC17 virus and tubastatin A (TBA) were injected into Thy1 Cre^ERT2-eYFP and Thy1-YFP mice to increase α-Ac-Tub expression. Single-pellet retrieval, irregular ladder walking, rotarod, and cylinder tests were performed to test the motor function after the ischemic stroke.

Results

α-Ac-Tub was colocalized with postsynaptic density 95. Although knockout of MEC17 in the pyramidal neurons did not affect the density of the dendritic spines, it significantly aggravated the injury to them in the penumbra area and motor dysfunction after stroke. However, MEC17 upregulation in the pyramidal neurons and TBA treatment could maintain mature dendritic spine density and alleviate motor dysfunction after stroke.

Conclusion

Our study demonstrated that α-Ac-Tub plays a crucial role in the maintenance of the structure and functions of mature dendritic spines. Moreover, α-Ac-Tub protected the dendritic spines in the penumbra area and alleviated motor dysfunction after stroke.     

Macrophage migration inhibitory factor promotes cell death and aggravates neurologic deficits after experimental stroke

Multiple mechanisms contribute to tissue demise and functional recovery after stroke. We studied the involvement of macrophage migration inhibitory factor (MIF) in cell death and development of neurologic deficits after experimental stroke. Macrophage migration inhibitory factor is upregulated in the brain after cerebral ischemia, and disruption of the Mif gene in mice leads to a smaller infarct volume and better sensory-motor function after transient middle cerebral artery occlusion (tMCAo). In mice subjected to tMCAo, we found that MIF accumulates in neurons of the peri-infarct region, particularly in cortical parvalbumin-positive interneurons. Likewise, in cultured cortical neurons exposed to oxygen and glucose deprivation, MIF levels increase, and inhibition of MIF by (S,R)-3-(4-hydroxyphenyl)-4,5-dihydro-5-isoxazole acetic acid methyl ester (ISO-1) protects against cell death. Deletion of MIF in Mif^−/− mice does not affect interleukin-1β protein levels in the brain and serum after tMCAo. Furthermore, disruption of the Mif gene in mice does not affect CD68, but it is associated with higher galectin-3 immunoreactivity in the brain after tMCAo, suggesting that MIF affects the molecular/cellular composition of the macrophages/microglia response after experimental stroke. We conclude that MIF promotes neuronal death and aggravates neurologic deficits after experimental stroke, which implicates MIF in the pathogenesis of neuronal injury after stroke.