Severe perinatal hypoxia-ischemia is an important cause of brain injury in both full-term and premature newborns, with a high risk of future behavioral and neurological deficits. The most commonly used animal model of neonatal hypoxia-ischemia is the unilateral ligation of the common carotid artery followed by exposure to hypoxia in 7-day-old rats. In spite of the wide use of this model, lot of contradictions and discrepancies exist between the results obtained by different laboratories regarding behavioral deficits and there are no data regarding the possible delay of the appearance of neurological reflexes and the time-course of reflex performances following neonatal hypoxic-ischemic injury in rats. In the present study we showed that neonatal hypoxia-ischemia retarded the development of somatic growth and several neurological reflexes (ear twitch, grasping, gait and negative geotaxis). Hypoxic animals also displayed retarded performance in righting, geotaxis and gait reflexes. Although hypoxic pups performed worse in most tests for motor coordination, they reached normal levels by 5 weeks of age except in the footfault test. In the open-field, hypoxic animals were generally more active, except at 3 weeks, when activity of normal pups increased enormously as well. Brain areas were significantly reduced in hypoxic animals, but no close correlation was found with behavioral deficits.

A wealth of evidence associates disruptions of the parent-infant relationship (e.g. childhood parental loss or parental neglect) with the later appearance of panic disorder. In rodents, neonatal maternal separation and maternal deprivation (MD) are reported to increase the expression of anxiety-related defensive responses in adult animals. However, little is known about the long-term consequences of these early-life stressors in animal models of panic. We here investigated the effects of a single 24 h-episode of MD on post-natal day 11 (PND 11) in adult male Wistar rats submitted to two animal models that associate escape expression with panic attacks: the elevated T-maze and exposure to severe hypoxia (7% O2). We also investigated the involvement of serotonin (5-HT) in the observed changes. Although neonatal MD did not affect the behavioral responses measured in the elevated T-maze, it facilitated the expression of escape during hypoxia exposure, indicating a panicogenic-like effect. Pre-test administration of the 5-HT synthesis inhibitor, para-chlorophenylalanine (PCPA; 4 daily injections of 100 mg/kg) facilitated escape attempts in non-deprived animals during the hypoxia challenge, but did not interfere with the expression of this behavior in maternally-deprived rats. The levels of 5-HT1A receptors in key panic- and anxiety-associated areas, the dorsal periaqueductal gray and amygdala, respectively, were not different between previously deprived and non-deprived animals. Plasma corticosterone levels were significantly increased by hypoxia exposure, independently of the animals' previous stress condition or PCPA administration. Therefore, MD on PND 11 predisposes the adult animal to the panic-evoking effects of severe hypoxia, a stimulus also reported to induce panic attacks in humans. The lack of PCPA effect on the pro-escape consequence of MD may be indicative that 5-HT signaling is impaired in the stressed animal.

Vascular pathologies represent the leading causes of mortality worldwide. The nervous system has evolved mechanisms to compensate for the cerebral hypoxia caused by many of these conditions. Vessel dilation and growth of new vessels are two prominent responses to hypoxia, both of which play a critical role in maintaining cerebral homeostasis. One way to facilitate cerebrovascular plasticity, and develop neuroprotection against vascular pathologies, is through aerobic exercise. The present study explored the long-term consequences of aerobic exercise on vascular structure and function in the motor cortex. Rats were assigned to a sedentary condition or were provided access to running wheels for 26 weeks. Rats were then anesthetized, and angiograms were captured using spectral domain optical coherence tomography (SD-OCT) to explore cerebrovascular reactivity in response to altered oxygen and carbon dioxide status. Following this procedure, all rats were euthanized, and unbiased stereological quantification of blood vessel density was collected from sections of the primary motor cortex infused with India ink. Results demonstrated that chronic exercise increased capillary and arteriole surface area densities and enhanced arteriole reactivity in response to hypercapnia-hypoxia, as displayed by increased vasodilation within the motor cortex of exercised animals.

There is an urgent need for therapies that could reduce the disease burden of preterm hypoxic-ischemic encephalopathy. Here, we evaluate the long-term effects of multipotent adult progenitor cells (MAPC) on long-term behavioral outcomes in a preterm rat model of perinatal asphyxia. Rats of both sexes were treated with two doses of MAPCs within 24 h after the insult. Locomotor, cognitive and psychiatric impairments were evaluated starting at 1.5 (juvenile) and 6 months (adult). Hypoxia-ischemia affected locomotion, cognition, and anxiety in a sex-dependent manner, with higher vulnerability observed in males. The MAPC therapy partially attenuated deficits in object recognition memory in females of all tested ages, and in the adult males. The hypoxic insult caused delayed hyperactivity in adult males, which was corrected by MAPC therapy. These results suggest that MAPCs may have long-term benefits for neurodevelopmental outcome after preterm birth and global hypoxia-ischemia, which warrants further preclinical exploration.

Early ethanol exposure alters neonatal breathing plasticity. Respiratory EtOH's effects are attributed to central respiratory network disruptions, particularly in the medullary serotonin (5HT) system. In this study we evaluated the effects of neonatal pre-exposure to low/moderate doses upon breathing rates, activation patterns of brainstem's nuclei and expression of 5HT 2A and 2C receptors. At PD9, breathing frequencies, tidal volumes and apneas were examined in pups pre-exposed to vehicle or ethanol (2.0 g/kg) at PDs 3, 5 and 7. This developmental stage is equivalent to the 3rd human gestational trimester, characterized by increased levels of synaptogenesis. Pups were tested under sobriety or under the state of ethanol intoxication and when subjected to normoxia or hypoxia. Number of c-Fos and 5HT immunolabelled cells and relative mRNA expression of 5HT 2A and 2C receptors were quantified in the brainstem. Under normoxia, ethanol pre-exposed pups exhibited breathing depressions and a high number of apneas. An opposite phenomenon was found in ethanol pre-treated pups tested under hypoxia where an exacerbated hypoxic ventilatory response (HVR) was observed. The breathing depression was associated with an increase in the neural activation levels of the raphe obscurus (ROb) and a high mRNA expression of the 5HT 2A receptor in the brainstem while desactivation of the ROb and high activation levels in the solitary tract nucleus and area postrema were associated to the exacerbated HVR. In summary, early ethanol experience induces respiratory disruptions indicative of sensitization processes. Neuroadaptive changes in central respiratory areas under consideration appear to be strongly associated with changes in their respiratory plasticity.

Obstetric complications, like maternal hypertension and neonatal hypoxia, disrupt brain development, leading to psychiatry disorders later in life, like schizophrenia. The exact mechanisms behind this risk are not yet well known. Spontaneously hypertensive rats (SHR) are a well-established model to study neurodevelopment of schizophrenia since they exhibit behavioral alterations mimicking schizophrenia that can be improved with antipsychotic drugs. SHR mothers are hypertensive, and the SHR offspring develop in preeclampsia-like conditions. Hypoxic conditions increase levels of adenosine, which play an important role in brain development. The enhanced levels of adenosine at birth could be related to the future development of schizophrenia. To investigate this hypothesis adenosine levels of brain neonatal Wistar rats and SHR were quantified. After that, caffeine, an antagonist of adenosinergic system, was administrated on PND (postnatal day) 7 (neurodevelopmental age similar to a human at delivery) and rats were observed at adolescent and adult ages. We also investigated the acute effects of caffeine at adolescent and adult ages. SHR control adolescent and adult groups presented behavioral deficits like hyperlocomotion, deficit in social interaction (SI), and contextual fear conditioning (CFC). In SHR, neonatal caffeine treatment on PND 7 normalized hyperlocomotion, improved SI, and CFC observed at adolescent period and adult ages, showing a beneficial effect on schizophrenia-like behaviors. Wistar rats neonatally treated with caffeine exhibited hyperlocomotion, deficit in SI and CFC when observed at adolescent and adult ages. Acutely caffeine treatment administrated at adolescent and adult ages increased locomotion and decreased SI time of Wistar rats and impair CFC in adult Wistars. No effects were observed in SHR. In conclusion, caffeine can be suggested as a useful drug to prevent behavioral deficits observed in this animal model of prenatal hypoxia-induced schizophrenia profile when specifically administered on PND 7.

Systematically distinguishing genetic liability from other contributing factors is critical for designing a preventive strategy for post-traumatic stress disorder (PTSD). To address this issue, we investigated a murine model exposing C57BL/6j, DBA/2j and BALB/cj mice to repeated stress via exposure to conspecific aggressors (Agg-E). Naïve mice from each strain were subjected to the proximity of aggressor (Agg) mice for 6h using a 'cage-within-a-cage' paradigm, which was repeated for 5 or 10 days with intermittent and unpredictable direct contact with Agg mice. During the Agg-E stress, DBA/2j developed a different strategy to evade Agg mice, which potentially contributed to its phenotypic resilience to Agg-E stress. Although Agg mice inflicted C57BL/6j and BALB/cj with equivalent numbers of strikes, BALB/cj displayed a distinct behavioral phenotype with delayed exhibition of a number of PTSD-like features. By contrast, C57BL/6j mice displayed unique vulnerability to Agg-E stress induced myocardopathy, possibly attributable to their particular susceptibility to hypoxia. A group of genes (Bdnf, Ngf, Zwint, Cckbr, Slc6a4, Fkbp5) linked to PTSD and synaptic plasticity were significantly altered in C57BL/6j and BALB/cj Agg-E mice. Contributions of Agg-E stress history and genotypic heterogeneity emerged as the key mediators of PTSD-like features. Linking genetic components to specific phenotypic and pathological features could have potential clinical implications.

Neonatal hypoxic ischemia encephalopathy (HIE) leads to major deficits in language development. While clinically there is a known correlation in the degree of HIE injury and subsequent language disability, there are no treatments beyond speech and language therapy; therefore, experimental studies with a HIE animal model to test new interventions and therapeutics are warranted. Neonatal rodents normally ultrasonically vocalize at postnatal day 7 (PND 7) to PND 14 in response to removal from their mothers. At 6-8 weeks of age juvenile male rodents ultrasonically vocalize in response to exposure to a mature female mouse. Changes in ultrasonic vocalization (USV) production after neonatal brain injury, such ashypoxic ischemia (HI), have not been studied. This study examines the acute and long-term ultrasonic vocalization ability of mice after HI at PND 10. Pups were subjected to HI, sham, or naïve conditions; where in HI and sham surgeries the right common carotid artery was exposed, in the HI this artery was double ligated. The HI and sham pups were then exposed to60minof hypoxia. Naïve pups did not undergo surgery and were subjected to60minof room air. At 3 days following surgery, HI and sham pups vocalize less than nonsurgical naïve controls; yet "juvenile" mice of 6-8 weeks old that underwent HI at PND 10 vocalize less than sham and naïve mice. We conclude that HI injury has significant impact on later adult vocalization.

Chronic cerebral hypoperfusion (CCH) been well characterized as a common pathological status contributing to neurodegenerative diseases such as Alzheimer's disease and vascular dementia. CCH is an important factor that leads to cognitive impairment, but the underlying neurobiological mechanism is poorly understood and no effective treatment is available. Recently, transient receptor potential melastatin 4 (TRPM4) cation channel has been identified as an important molecular element in focal cerebral ischemia. Over activation of the channel is a major molecular mechanism of oncotic cell death. However, the role of TRPM4 in CCH that propagates global brain hypoxia have not been explored. Therefore, the present study is designed to investigate the effect of TRPM4 inhibition on the cognitive functions of the rats following CCH via permanent bilateral occlusion of common carotid arteries (PBOCCA) model. In this model, treatment with siRNA suppressed TRPM4 expression at both the mRNA and protein levels and improved cognitive deficits of the CCH rats without affecting their motor function. Furthermore, treatment with siRNA rescued the LTP impairment in CCH-induced rats. Consistent with the restored of LTP, western blot analysis revealed that siRNA treatment prevented the reduction of synaptic proteins, including calcium/calmodulin-dependent kinase II alpha (CaMKIIα) and brain-derived neurotrophic factor (BDNF) in brain regions of CCH rats. The present findings provide a novel role of TRPM4 in restricting cognitive functions in CCH and suggest inhibiting TRPM4 may represent a promising therapeutic strategy in targeting ion channels to prevent the progression of cognitive deficits induced by ischemia.