Glutamatergic VP neurons constitute a noncanonical subpopulation of VP neurons. These glutamatergic VP neurons increase activity of the lateral habenula, rostromedial tegmental nucleus, and gamma-aminobutyric acidergic ventral tegmental area neurons and adaptively constrain reward seeking.
Our data indicate that female mice exposed to ES display a behavioral and physiologic profile that mimics symptoms of depression in the clinical population. As such, this experimental model may be adopted to examine vicarious stress-induced mood-related disorders, as well as pharmacological antidepressant response, in a sex-specific manner.
Social stress, including bullying during adolescence, is a risk factor for common psychopathologies such as depression. To investigate the neural mechanisms associated with juvenile social stress-induced mood-related endophenotypes, we examined the behavioral, morphological, and biochemical effects of the social defeat stress model of depression on hippocampal dendritic spines within the CA1 stratum radiatum. Adolescent (postnatal day 35) male C57BL/6 mice were subjected to defeat episodes for 10 consecutive days. Twenty-four h later, separate groups of mice were tested on the social interaction and tail suspension tests.Hippocampi were then dissected and Western blots were conducted to quantify protein levels for various markers important for synaptic plasticity including protein kinase M zeta (PKMζ), protein kinase C zeta (PKCζ), the dopamine-1 (D1) receptor, tyrosine hydroxylase (TH), and the dopamine transporter (DAT). Furthermore, we examined the presence of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-receptor subunit GluA2 as well as colocalization with the post-synaptic density 95 (PSD95) protein, within different spine subtypes (filopodia, stubby, long-thin, mushroom) using an immunohistochemistry and Golgi-Cox staining technique. The results revealed that social defeat induced a depression-like behavioral profile, as inferred from decreased social interaction levels, increased immobility on the tail suspension test, and decreases in body weight. Whole hippocampal immunoblots revealed decreases in GluA2, with a concomitant increase in DAT and TH levels in the stressed group. Spine morphology analyses further showed that defeated mice displayed a significant decrease in stubby spines, and an increase in long-thin spines within the CA1 stratum radiatum. Further evaluation of GluA2/PSD95 containing-spines demonstrated a decrease of these markers within long-thin and mushroom spine types. Together, these results indicate that juvenile social stress induces GluA2- and dopamine-associated dysregulation in the hippocampus – a neurobiological mechanism potentially underlying the development of mood-related syndromes as a consequence of adolescent bullying.
Opioid use by pregnant women is an understudied consequence associated with the opioid epidemic, resulting in a rise in the incidence of neonatal opioid withdrawal syndrome (NOWS) and lifelong neurobehavioral deficits that result from perinatal opioid exposure. There are few preclinical models that accurately recapitulate human perinatal drug exposure and few focus on fentanyl, a potent synthetic opioid that is a leading driver of the opioid epidemic. To investigate the consequences of perinatal opioid exposure, we administered fentanyl to mouse dams in their drinking water throughout gestation and until litters were weaned at postnatal day (PD) 21. Fentanyl‐exposed dams delivered smaller litters and had higher litter mortality rates compared with controls. Metrics of maternal care behavior were not affected by the treatment, nor were there differences in dams' weight or liquid consumption throughout gestation and 21 days postpartum. Twenty‐four hours after weaning and drug cessation, perinatal fentanyl‐exposed mice exhibited signs of spontaneous somatic withdrawal behavior and sex‐specific weight fluctuations that normalized in adulthood. At adolescence (PD 35), they displayed elevated anxiety‐like behaviors and decreased grooming, assayed in the elevated plus maze and sucrose splash tests. Finally, by adulthood (PD 55), they displayed impaired performance in a two‐tone auditory discrimination task. Collectively, our findings suggest that perinatal fentanyl‐exposed mice exhibit somatic withdrawal behavior and change into early adulthood reminiscent of humans born with NOWS.
One consequence of the opioid epidemic are the lasting neurodevelopmental sequelae afflicting children and adolescents exposed to opioids in the womb. The gravity of these consequences is further amplified by the COVID-19 pandemic, in which the use of synthetic opioids, including fentanyl, has increased among pregnant women. A translationally relevant and developmentally accurate preclinical model is needed to understand the behavioral, circuit, network, and molecular abnormalities resulting from fentanyl use during pregnancy. By employing a novel preclinical model of perinatal fentanyl exposure, our data reveal that fentanyl has several dose-dependent, developmental consequences to somatosensory function and behavior. First, newborn mice exhibit signs of withdrawal, and sensory-related deficits that extend at least to adolescence. As fentanyl exposure does not affect dams’ health or maternal behavior, these effects appear to result from the direct actions of perinatal fentanyl on the pups’ developing brain. At adolescence, exposed mice exhibited reduced adaptation to sensory stimuli, and a corresponding impairment in primary somatosensory (S1) function. Our in vitro electrophysiology data demonstrate that perinatal fentanyl leads to a long-lasting reduction in S1 synaptic excitation, as evidenced by decreases in excitatory release probability, NMDA receptor-mediated postsynaptic currents, and frequency of miniature excitatory postsynaptic currents, as well as increased frequency of miniature inhibitory postsynaptic currents. In contrast, anterior cingulate cortical neurons exhibit an opposite phenotype, with increased synaptic excitation in perinatal fentanyl exposed mice. Consistent with these synaptic changes, analysis of electrocorticograms revealed that exposed adolescent mice exhibited suppressed ketamine-evoked γ oscillations. Morphological analysis of S1 pyramidal neurons from exposed mice indicate reduced dendritic complexity, dendritic length, and soma size. Further, exposed mice exhibited abnormal cortical mRNA expression of key receptors involved in synaptic transmission and neuronal growth and development, changes that were consistent with the electrophysiological and morphological changes. These findings demonstrate the lasting sequela of perinatal fentanyl exposure on sensory processing and function.
Opioid use by pregnant women is an understudied consequence associated with the opioid epidemic, resulting in a rise in the incidence of neonatal opioid withdrawal syndrome (NOWS), and lifelong neurobehavioral deficits that result from perinatal opioid exposure. There are few preclinical models that accurately recapitulate human perinatal drug exposure, and few focus on fentanyl, a potent synthetic opioid that is a leading driver of the opioid epidemic. To investigate the consequences of perinatal opioid exposure, we administered fentanyl to mouse dams in their drinking water throughout gestation and until litters were weaned at postnatal day (PD) 21. Fentanyl-exposed dams delivered smaller litters, and had higher litter mortality rates compared to controls.Metrics of maternal care behavior were not affected by the treatment, nor were there differences in dams' weight or liquid consumption throughout gestation and 21 days postpartum. Twenty-four hours after weaning and drug cessation, perinatal fentanyl-exposed mice exhibited signs of spontaneous somatic withdrawal behavior, and sex-specific weight fluctuations that normalized in adulthood. At adolescence (PD 35) they displayed elevated anxiety-like behaviors and decreased grooming, assayed in the elevated plus maze and sucrose splash tests. Finally, by adulthood (PD 55) they displayed impaired performance in a two-tone auditory discrimination task. Collectively, our findings suggest that perinatal fentanyl exposed mice exhibit somatic withdrawal behavior and changes across the lifespan reminiscent of humans born with NOWS.Within this growing crisis, individuals between the age of 18 and 25 have exhibited the largest increase in illicit opioid use (Substance Abuse and Mental Health Services Administration, 2013). It is concerning that women of reproductive age show increased incidence of use, given that opioids -both natural and synthetic -can readily cross the placenta and the blood-brain barrier. Indeed, in utero opioid exposure is associated with deleterious effects in developing offspring, with more dramatic effects on neurological function observed in infants relative to adults. 3 There has been an exponential increase in the distribution of the synthetic opioid, fentanyl, which is routinely incorporated into frequently used narcotics, such as heroin. 4 Fentanyl is 50 to 100 times more potent than morphine and is chiefly responsible for the recent increase in synthetic opioid-related overdose deaths. 5 The effects that synthetic opioids have on the developmental trajectory of offspring have been incompletely studied, and are critically needed to develop effective treatment and prevention plans.Women who used opioids during pregnancy have an increased rate of undergoing premature birth, stillbirth, and infant death. 6 Withdrawal symptoms occur in 30-80% of neonates exposed to opioids in utero, 7 and they exhibit decreased birth weight and body size. 8 Consequences may be long lasting, as children and adolescents exposed to pre and peri-natal opioids have disr...
Background: Epidemiological reports indicate that mood-related disorders are common in the adolescent population. The prevalence of juvenile major depressive disorder has resulted in a parallel increase in the prescription rates of fluoxetine (FLX) within this age group. Although such treatment can last for years, little is known about the enduring consequences of adolescent antidepressant exposure on memory-related performance. Methods:We exposed separate groups of adolescent (postnatal day [PD] 35) male and female C57BL/6 mice to FLX (20 mg/kg) for 15 consecutive days (PD35-49). Three weeks after FLX exposure (PD70), we assessed learning and memory performance on a single-day training object novelty recognition test, or a spatial memory task on the Morris water maze (MWM). Results:We found that FLX pretreatment did not influence performance on either the object novelty recognition task or the MWM, 24 hr after training. Conversely, 48 hr post spatial-training on the MWM, FLX pretreated male mice spent significantly less time on the quadrant of the missing platform during a standard probe trial. No differences in MWM performance were observed in the adult female mice pretreated with FLX.
One consequence of the opioid epidemic are lasting neurodevelopmental sequelae afflicting adolescents exposed to opioids in the womb. A translationally relevant and developmentally accurate preclinical model is needed to understand the behavioral, circuit, network, and molecular abnormalities resulting from this exposure. By employing a novel preclinical model of perinatal fentanyl exposure, our data reveal that fentanyl has several dose-dependent, developmental consequences to somatosensory function and behavior. Newborn male and female mice exhibit signs of withdrawal and sensory-related deficits that extend at least to adolescence. As fentanyl exposure does not affect dams' health or maternal behavior, these effects result from the direct actions of perinatal fentanyl on the pups' developing brain. At adolescence, exposed mice exhibit reduced adaptation to sensory stimuli, and a corresponding impairment in primary somatosensory (S1) function. In vitro electrophysiology demonstrates a long-lasting reduction in S1 synaptic excitation, evidenced by decreases in release probability, NMDA receptor-mediated postsynaptic currents, and frequency of miniature excitatory postsynaptic currents (mEPSCs), as well as increased frequency of miniature inhibitory postsynaptic currents (mIPSCs). In contrast, anterior cingulate cortical neurons exhibit an opposite phenotype, with increased synaptic excitation. Consistent with these changes, electrocorticograms (ECoGs) reveal suppressed ketamine-evoked c oscillations. Morphologic analysis of S1 pyramidal neurons indicate reduced dendritic complexity, dendritic length, and soma size. Further, exposed mice exhibited abnormal cortical mRNA expression of key receptors involved in synaptic transmission and neuronal growth and development, changes that were consistent with the electrophysiological and morphologic changes. These findings demonstrate the lasting sequelae of perinatal fentanyl exposure on sensory processing and function.
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