scholarly journals Amygdalar Corticotropin-Releasing Factor Signaling Is Required for Later-Life Behavioral Dysfunction Following Neonatal Pain

2021 ◽  
Vol 12 ◽  
Author(s):  
Seth M. Davis ◽  
Jared T. Zuke ◽  
Mariah R. Berchulski ◽  
Michael A. Burman
Keyword(s):  
Receptor Antagonist ◽  
Fear Conditioning ◽  
Later Life ◽  
Corticotropin Releasing Factor ◽  
Female Rats ◽  
Central Nucleus ◽  
Neonatal Pain ◽  
Stage Of Development ◽  
Male And Female Rats ◽  
Crf System

Neonatal pain such as that experienced by infants in the neonatal intensive care unit is known to produce later-life dysfunction including heightened pain sensitivity and anxiety, although the mechanisms remain unclear. Both chronic pain and stress in adult organisms are known to influence the corticotropin-releasing factor (CRF) system in the Central Nucleus of the Amygdala, making this system a likely candidate for changes following neonatal trauma. To examine this, neonatal rats were subjected to daily pain, non-painful handling or left undisturbed for the first week of life. Beginning on postnatal day, 24 male and female rats were subjected to a 4-day fear conditioning and sensory testing protocol. Some subjects received intra-amygdalar administration of either Vehicle, the CRF receptor 1 (CRF1) receptor antagonist Antalarmin, or the CRF receptor 2 (CRF2) receptor antagonist Astressin 2B prior to fear conditioning and somatosensory testing, while others had tissue collected following fear conditioning and CRF expression in the CeA and BLA was assessed using fluorescent in situ hybridization. CRF1 antagonism attenuated fear-induced hypersensitivity in neonatal pain and handled rats, while CRF2 antagonism produced a general antinociception. In addition, neonatal pain and handling produced a lateralized sex-dependent decrease in CRF expression, with males showing a diminished number of CRF-expressing cells in the right CeA and females showing a similar reduction in the number of CRF-expressing cells in the left BLA compared to undisturbed controls. These data show that the amygdalar CRF system is a likely target for alleviating dysfunction produced by early life trauma and that this system continues to play a major role in the lasting effects of such trauma into the juvenile stage of development.

Effects of rearing temperature on body weight and abdominal fat in male and female rats

1998 ◽  
Vol 274 (2) ◽  
pp. R398-R405 ◽  
Author(s):  
James B. Young ◽  
Yasunobu Shimano
Keyword(s):  
Weight Gain ◽  
Later Life ◽  
Female Rats ◽  
Male Rats ◽  
Fat Accumulation ◽  
Rearing Temperature ◽  
Male And Female Rats ◽  
Postnatal Environment ◽  
Temperature Exposure ◽  
The Impact

Thermoregulatory mechanisms are influenced by the temperature of the postnatal environment. Animals reared in cool environments are more tolerant of cold as adults, whereas those reared in warm conditions are more tolerant of heat. Because diet-induced and thermoregulatory thermogenesis share common features, studies examined the impact of rearing temperature on weight gain and fat accumulation. Rats reared at 18°C gained more weight and accumulated more fat in abdominal depots than animals reared at 30°C when both were housed at a common temperature, responses that were exacerbated by ad libitum access to sucrose. Male rats reared at 30°C were less affected by sucrose than 18°C-reared males, whereas female rats reared at 18 or 30°C were similarly susceptible. During exposure to 18°C, fat accumulation in abdominal depots increased in males but decreased in females. These data suggest that early temperature exposure influences weight gain and fat accumulation in later life, a difference that is most apparent when animals are housed at a common temperature.

scholarly journals Proteomic Analysis Reveals Sex-Specific Protein Degradation Targets in the Amygdala During Fear Memory Formation

2021 ◽  
Vol 14 ◽  
Author(s):  
Kayla Farrell ◽  
Madeline Musaus ◽  
Shaghayegh Navabpour ◽  
Kiley Martin ◽  
W. Keith Ray ◽  
...  
Keyword(s):  
Protein Degradation ◽  
Fear Conditioning ◽  
Degradation Process ◽  
Fear Memory ◽  
Memory Formation ◽  
Contextual Fear Conditioning ◽  
Female Rats ◽  
Protein Targets ◽  
Male And Female Rats ◽  
Ubiquitin Proteasome

Ubiquitin-proteasome mediated protein degradation has been widely implicated in fear memory formation in the amygdala. However, to date, the protein targets of the proteasome remain largely unknown, limiting our understanding of the functional significance for protein degradation in fear memory formation. Additionally, whether similar proteins are targeted by the proteasome between sexes has yet to be explored. Here, we combined a degradation-specific K48 Tandem Ubiquitin Binding Entity (TUBE) with liquid chromatography mass spectrometry (LC/MS) to identify the target substrates of the protein degradation process in the amygdala of male and female rats following contextual fear conditioning. We found that males (43) and females (77) differed in the total number of proteins that had significant changes in K48 polyubiquitin targeting in the amygdala following fear conditioning. Many of the identified proteins (106) had significantly reduced levels in the K48-purified samples 1 h after fear conditioning, suggesting active degradation of the substrate due to learning. Interestingly, only 3 proteins overlapped between sexes, suggesting that targets of the protein degradation process may be sex-specific. In females, many proteins with altered abundance in the K48-purified samples were involved in vesicle transport or are associated with microtubules. Conversely, in males, proteins involved in the cytoskeleton, ATP synthesis and cell signaling were found to have significantly altered abundance. Only 1 protein had an opposite directional change in abundance between sexes, LENG1, which was significantly enhanced in males while lower in females. This suggests a more rapid degradation of this protein in females during fear memory formation. Interestingly, GFAP, a critical component of astrocyte structure, was a target of K48 polyubiquitination in both males and females, indicating that protein degradation is likely occurring in astrocytes following fear conditioning. Western blot assays revealed reduced levels of these target substrates following fear conditioning in both sexes, confirming that the K48 polyubiquitin was targeting these proteins for degradation. Collectively, this study provides strong evidence that sex differences exist in the protein targets of the degradation process in the amygdala following fear conditioning and critical information regarding how ubiquitin-proteasome mediated protein degradation may contribute to fear memory formation in the brain.

Effects of the glucocorticoid receptor antagonist PT150 on stress-induced fentanyl seeking in male and female rats

2021 ◽  
Author(s):  
Lindsey R. Hammerslag ◽  
Emily D. Denehy ◽  
Benjamin Carper ◽  
Tracy L. Nolen ◽  
Mark A. Prendergast ◽  
...  
Keyword(s):  
Glucocorticoid Receptor ◽  
Receptor Antagonist ◽  
Female Rats ◽  
Male And Female ◽  
Male And Female Rats

Effects of corticotropin-releasing factor on energy balance in rats are sex dependent

1989 ◽  
Vol 257 (6) ◽  
pp. R1417-R1422 ◽  
Author(s):  
S. Rivest ◽  
Y. Deshaies ◽  
D. Richard
Keyword(s):  
Body Weight ◽  
Energy Balance ◽  
Food Intake ◽  
Serum Testosterone ◽  
Corticotropin Releasing Factor ◽  
Female Rats ◽  
Male Rats ◽  
Male And Female ◽  
Male And Female Rats ◽  
Significant Difference

The purpose of this study was to investigate the effects of a chronic intracerebroventricular administration of corticotropin-releasing factor (CRF) on energy balance of male and female rats. One week after their delivery to the laboratory, both male and female rats were divided into two groups. One group in each sex was treated with human/rat CRF, while another group was infused with the vehicle. Chronic administration of CRF was accomplished by means of miniosmotic pumps connected to a cannula that was stereotaxically directed into the third ventricle. Food intake and body weight were measured each day during the study. After 14 days of treatment, the rats were killed by decapitation. Energy, fat, and protein contents of the carcasses were quantified. Serum testosterone and estradiol were assayed in males and females, respectively. Administration of CRF significantly reduced body weight gain and food intake in male rats. No significant difference in those variables was observed between female rats treated with CRF and their controls infused with saline. Similarly, metabolizable energy intake and body energy gain were reduced in male rats infused with CRF, whereas no difference was observed between female animals treated with CRF and those infused with saline. In male rats, body fat and body protein contents were lower in CRF-treated than in saline-infused rats. In female rats, CRF did not affect body composition. Serum testosterone in male rats and serum estradiol in female animals were reduced after chronic infusion of CRF.(ABSTRACT TRUNCATED AT 250 WORDS)

scholarly journals Fear Extinction and Predictive Trait-Like Inter-Individual Differences in Rats Lacking the Serotonin Transporter

2021 ◽  
Vol 22 (13) ◽  
pp. 7088
Author(s):  
Maria Willadsen ◽  
Metin Üngör ◽  
Anna Sługocka ◽  
Rainer K. W. Schwarting ◽  
Judith R. Homberg ◽  
...  
Keyword(s):  
Individual Differences ◽  
Fear Conditioning ◽  
Pain Sensitivity ◽  
Fear Extinction ◽  
Female Rats ◽  
Novelty Seeking ◽  
Conditioning Paradigm ◽  
Predictive Quality ◽  
Male And Female Rats ◽  
Wildtype Littermate

Anxiety disorders are associated with a failure to sufficiently extinguish fear memories. The serotonergic system (5-hydroxytryptamine, 5-HT) with the 5-HT transporter (5-HTT, SERT) is strongly implicated in the regulation of anxiety and fear. In the present study, we examined the effects of SERT deficiency on fear extinction in a differential fear conditioning paradigm in male and female rats. Fear-related behavior displayed during acquisition, extinction, and recovery, was measured through quantification of immobility and alarm 22-kHz ultrasonic vocalizations (USV). Trait-like inter-individual differences in novelty-seeking, anxiety-related behavior, habituation learning, cognitive performance, and pain sensitivity were examined for their predictive value in forecasting fear extinction. Our results show that SERT deficiency strongly affected the emission of 22-kHz USV during differential fear conditioning. During acquisition, extinction, and recovery, SERT deficiency consistently led to a reduction in 22-kHz USV emission. While SERT deficiency did not affect immobility during acquisition, genotype differences started to emerge during extinction, and during recovery rats lacking SERT showed higher levels of immobility than wildtype littermate controls. Recovery was reflected in increased levels of immobility but not 22-kHz USV emission. Prominent sex differences were evident. Among several measures for trait-like inter-individual differences, anxiety-related behavior had the best predictive quality.

scholarly journals Behavioral and brain mechanisms mediating conditioned flight behavior in rats

2021 ◽  
Author(s):  
Michael S. Totty ◽  
Naomi Warren ◽  
Isabella Huddleston ◽  
Karthik R. Ramanathan ◽  
Reed L. Ressler ◽  
...  
Keyword(s):  
Compound Stimulus ◽  
Female Rats ◽  
Flight Behavior ◽  
Central Nucleus ◽  
Stria Terminalis ◽  
Conditioning Context ◽  
Bed Nucleus ◽  
Contextual Fear ◽  
Male And Female Rats ◽  
Innate Fear

ABSTRACTEnvironmental contexts and associative learning can inform animals of potential threats, though it is currently unknown how contexts bias defensive transitions. Here we investigated context-dependent flight responses in the Pavlovian serial-compound stimulus (SCS) paradigm. We show here that SCS-evoked flight behavior in male and female rats is dependent on contextual fear. Flight was reduced in the conditioning context after context extinction and could be evoked in a different shock-associated context. Although flight was exclusive to white noise stimuli, it was nonetheless associative insofar as rats that received an equal number of unpaired USs did not show flight-like behavior. Finally, we found that inactivation of either the central nucleus of the amygdala (CeA) or bed nucleus of the stria terminalis (BNST) attenuated both contextual fear and flight responses. This work demonstrates that contextual fear summates with cued and innate fear to drive a high fear state and freeze-to-flight transitions.

scholarly journals Behavioral and brain mechanisms mediating conditioned flight behavior in rats

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Michael S. Totty ◽  
Naomi Warren ◽  
Isabella Huddleston ◽  
Karthik R. Ramanathan ◽  
Reed L. Ressler ◽  
...  
Keyword(s):  
Compound Stimulus ◽  
Brain Regions ◽  
Female Rats ◽  
Flight Behavior ◽  
Central Nucleus ◽  
Male And Female ◽  
Bed Nucleus ◽  
Contextual Fear ◽  
Male And Female Rats ◽  
Context Dependent

AbstractEnvironmental contexts can inform animals of potential threats, though it is currently unknown how context biases the selection of defensive behavior. Here we investigated context-dependent flight responses with a Pavlovian serial-compound stimulus (SCS) paradigm that evokes freeze-to-flight transitions. Similar to previous work in mice, we show that male and female rats display context-dependent flight-like behavior in the SCS paradigm. Flight behavior was dependent on contextual fear insofar as it was only evoked in a shock-associated context and was reduced in the conditioning context after context extinction. Flight behavior was only expressed to white noise regardless of temporal order within the compound. Nonetheless, rats that received unpaired SCS trials did not show flight-like behavior to the SCS, indicating it is associative. Finally, we show that pharmacological inactivation of two brain regions critical to the expression of contextual fear, the central nucleus of the amygdala (CeA) and bed nucleus of the stria terminalis (BNST), attenuates both contextual fear and flight responses. All of these effects were similar in male and female rats. This work demonstrates that contextual fear can summate with cued and innate fear to drive a high fear state and transition from post-encounter to circa-strike defensive modes.

scholarly journals A two-hit adversity model in developing rats reveals sex-specific impacts on prefrontal cortex structure and behavior

2020 ◽  
Author(s):  
Kelsea R. Gildawie ◽  
Lilly M. Ryll ◽  
Jessica C. Hexter ◽  
Shayna Peterzell ◽  
Alissa A. Valentine ◽  
...  
Keyword(s):  
Prefrontal Cortex ◽  
Maternal Separation ◽  
Structural Integrity ◽  
Later Life ◽  
Female Rats ◽  
Critical Periods ◽  
Early Life Adversity ◽  
Behavioral Dysfunction ◽  
Male And Female Rats ◽  
Adverse Experiences

AbstractAdversity early in life substantially impacts prefrontal cortex (PFC) development and vulnerability to later-life psychopathology. Importantly, repeated adverse experiences throughout childhood increase the risk for PFC-mediated behavioral deficits more commonly in women. Evidence from animal models points to effects of adversity on later-life neural and behavioral dysfunction; however, few studies have investigated the neurobiological underpinnings of sex-specific, long term consequences of multiple developmental stressors. We modeled early life adversity in rats via maternal separation (postnatal day (P)2-20) and juvenile social isolation (P21-35). Adult (P85) male and female rats were assessed for differences in the presence and structural integrity of PFC perineuronal nets (PNNs) enwrapping parvalbumin (PV)-expressing interneurons. PNNs are extracellular matrix structures formed during critical periods in postnatal development that play a key role in the plasticity of PV cells. Females – but not males – exposed to multiple hits of adversity demonstrated a reduction in PFC PV cells in adulthood. We also observed a sex-specific, potentiated reduction in PV+ PNN structural integrity. Moreover, correlations between neural disruption and hyperactivity/risk-assessment behavior were altered by adversity differently in males and females. These findings suggest a sex-specific impact of repeated adversity on neurostructural development and implicate PNNs as a contributor to associated behavioral dysfunction.

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