Biomedical subjects

Stephen C Gammie

Publications and source records attributed to Stephen C Gammie.

17 recordsLinked to original sources

PubMed2006

Maternal aggression: new insights from Egr-1.

Lactating mice display fierce aggression towards novel, male mice. This study compares neuronal activity in the brains of aggression-tested (T) and -untested (U) mice using early growth response factor 1 (Egr-1; also known as Krox 24, NGFI-A, Zif268, Tis8, and ZENK) as a measure of neuronal activity. Animals were sampled 90 min after either a sham or real 7-min test with a male intruder, after which their brains were examined for immunoreactivity to Egr-1 (Egr-IR). Significant increases in Egr-IR in T mice were identified in 11 of 40 brain regions, including paraventricular nucleus of the hypothalamus; anterior and lateral hypothalamus (both posterior portion); ventromedial hypothalamus; lateral periaqueductal gray; and medial, central, and basolateral amygdala. Posterodorsal (MePD) and posteroventral medial amygdala were examined for the first time in association with maternal aggression. MePD, a region associated with both sexual and aggressive behaviors in rats, hamsters, and mice, showed increased Egr-IR in association with testing. Taken together, the results from this study provide new insights into the neural circuits regulating maternal behaviors.

Aggression↗

PubMed2006

Intermale aggression in corticotropin-releasing factor receptor 1 deficient mice.

The anxiogenic neuropeptide, corticotropin-releasing factor (CRF), has a complex effect on intermale aggression. CRF receptor 1 (CRFR1) is the primary receptor for CRF and in this study, we examined in detail isolation-induced intermale aggression in CRFR1 deficient mice. All mice contained a mixed 50:50 inbred/outbred background to improve aggressive performance. Mice were isolated for 4 weeks prior to 2 consecutive days of aggression testing using the resident-intruder paradigm. Mice were also tested for anxiety on the elevated plus maze. Relative to littermate wild-type (WT) controls, CRFR1-mutant mice exhibited normal levels of intermale aggression over the 2 test days in terms of percentage showing aggression, number of attacks, time aggressive, and latency to first attack. In terms of sites of attacks on intruders, CRFR1-deficient mice attacked the ventral portion of the mid-section (including belly) significantly less frequently than WT males on test day 1, but these differences did not reach significance on test day 2. No other differences in sites of attacks were observed. Tail rattling also did not differ between groups. Importantly, KO males showed decreased anxiety relative to WT mice (consistent with previous reports) as evidenced by spending significantly more time on the open arms and significantly less time on the closed arms of the elevated plus maze. Plus maze performance did not correlate with any measure of levels of aggression, suggesting a dissociation between altered levels of anxiety and aggressive performance. Taken together, the results suggest that the activation CRFR1 is not necessary for the normal production of isolation-induced intermale aggression.

Aggression↗

PubMed2006

Artificial selection for increased maternal defense behavior in mice.

Maternal aggression is directed towards intruders by lactating females and is critical for defense of offspring. Within-family selection for increased maternal defense in outbred house mice (Mus domesticus; Hsd:ICR strain) was applied to one selected (S) line, using total duration of attacks in a 3-min test as the selection criterion. One control (C) line was maintained and both lines were propagated by 13 families in each generation. Prior to selection, heritability of maternal aggression was estimated to be 0.61 based on mother-offspring regression. Duration of attacks responded to selection with a mean realized heritability of 0.40 (corrected for within-family selection) after eight generations. At generation 5, the S and C line also differed significantly for litter size at birth and at mid-lactation (both lower in S), average individual pup mass at midlactation (higher in S), and pup retrieval latency (longer in S), but not for other maternal measures that we studied (e.g., dam mass). Additionally, number of entries to middle and closed plus maze compartments was significantly higher in S mice in Generation 5. This is the first study to select for high maternal defense and these mice will be made available as a tool for understanding the genetic and neural basis of maternal aggression.

Aggression↗

PubMed2006

Effects of daily and acute restraint stress during lactation on maternal aggression and behavior in mice.

A decreased reactivity to stressors during lactation might heighten the expression of maternal care (including defense of offspring) by minimizing the extent to which stress can impact maternal care. Although stressors applied during pregnancy have variable effects on maternal aggression (or defense of offspring), to date no study has examined the effects of stress applied during the postpartum period on maternal aggression. In this study, we examined the effects of both daily and acute restraint stress (30 min) applied postpartum on maternal aggression and other maternal behaviors. Daily restraint (ending 2 h before testing) did not alter any measure of maternal behavior, including nursing, licking and grooming of pups and pup retrieval, or any measure of maternal aggression. In contrast, acute stress significantly impaired total time aggressive and number of attacks, but pup retrieval was normal. c-Fos levels were significantly elevated in a number of brain regions in association with acute stress, including lateral septum (LS), caudal periaqueductal gray and medial amygdala (MeA), suggesting possible sites where stress reactivity could alter aggression. Together, the results indicate that acute restraint stress impairs maternal aggression and provide a starting point for future studies examining how stress reactivity pathways may intersect with maternal aggression pathways.

Aggression↗

PubMed2005

Gene array profiling of large hypothalamic CNS regions in lactating and randomly cycling virgin mice.

A dramatic example of neuronal and physiological plasticity in adult mammals occurs during the transition from a non-maternal to a maternal, lactating state. In this study, we compared gene expression within a large continuous region of the CNS involved in maternal behaviors (hypothalamus, preoptic regions, and nucleus accumbens) between lactating (L) (postpartum Day 7) and randomly cycling virgin (V) outbred mice. Using high-density oligonucleotide arrays representing 11,904 genes, two statistical algorithms were used to identify significant differences in gene expression: robust multiarray (P < 0.001) (n = 92 genes) and significance analysis of microarrays using a 10% false discover rate (n = 114 genes). 27 common genes were identified as significant using both techniques. A subset of genes (n = 5) were selected and examined by real-time PCR. Our findings were consistent with previous published work. For example, neuropeptide Y (NPY) and proenkephalin were elevated in L mice, whereas POMC was decreased. Increased levels of NPY Y2 receptor and polo-like kinase and decreased levels of endothelin receptor type b in L mice are examples of novel gene expression changes not previously identified. Expression differences occurred in broad classes. Together, our findings provide possible new material on gene expression changes that may support maternal behaviors. The advantages and drawbacks of sampling large CNS regions using arrays are discussed.

Animals↗

PubMed2005

Environmental enrichment alters plus maze, but not maternal defense performance in mice.

Maternal defense behavior (or maternal aggression) is a highly conserved behavior for protecting offspring that is normally associated with decreased fear and anxiety in rodent dams. Environmental enrichment can decrease indices of fearfulness and anxiety (and elevate novelty seeking) in laboratory animals. This study examined whether enrichment could alter levels of maternal aggression and elevated plus maze performance in lactating mice. One group of female mice was exposed to a series of novel objects for 1.5 months while the other group was not. As expected, mice that had been exposed to an enriched environment showed significantly more entries to and time on the open arms of an elevated plus maze while they were lactating. Enriched mice showed similar maze performances when tested 3 months later in a non-lactating state, even though enrichment had been removed for 3 months. Further, offspring of enriched dams exhibited maze performance similar to that of their dams, suggesting possible epigenetic influences on maze performance. In contrast, no differences in measures of maternal aggression or pup retrieval were detected between enriched and control lactating mice. Together, these results indicate that environmental enrichment has long lasting effects on plus maze performance, but does not alter maternal aggression. The findings also suggest that whatever neural pathways are altered by enrichment do not strongly overlap or regulate those governing maternal aggression.

Aggression↗

PubMed2005

Differential fos activation in virgin and lactating mice in response to an intruder.

Lactating (L) mice display fierce aggression towards novel, male mice, while virgin (V) mice do not. This study compares patterns of brain activation in V and L mice in response to a novel intruder using immunohistochemical detection of Fos (Fos-IR). Animals were sampled 120 min after either a sham or real 10 min test with a male intruder. L mice were aggressive towards intruders, but V mice were not. In general, Fos-IR for both groups increased with exposure to an intruder, with L mice showing higher increases in Fos-IR than V mice. In only medial preoptic nucleus and ventral portion of bed nucleus of stria terminalis (BNST) was Fos-IR significantly increased in both groups with testing. In V mice, testing resulted in Fos-IR increases in an additional 10 regions examined that did not reach significance in L mice, including lateral septum, lateral and medial preoptic areas, and anterior hypothalamus. Fos-IR also increased with testing in nine regions unique to L mice, including the mitral and granular layers of accessory olfactory bulb, regions of the amygdala, dorsal BNST, and caudal portions of the hypothalamic attack area. These increases in Fos-IR with testing suggest alterations in the circuitry governing response to pheromonal cues and imply some commonalities between the circuitries governing maternal aggression and intermale aggression. These results support the hypothesis that pregnancy and lactation induce substantial changes in brain circuitry and function; changes that enable maternal defense of offspring by altering the neural response to an intruder male.

Aggression↗

PubMed2005

Urocortin 1 and 3 impair maternal defense behavior in mice.

Lactating female mice fiercely defend offspring while exhibiting decreased fear and anxiety. Recent work (J. S. Lonstein & S. C. Gammie, 2002) found that intracerebroventricular (icv) injections of corticotropin releasing factor (CRF), a putative anxiogenic peptide, inhibit maternal defense behavior. This study examines effects of CRF-related peptides, urocortin (Ucn) 1 and Ucn 3, on maternal aggression in mice. Intracerebroventricular injections of both Ucn 1 (0.2 microg) and Ucn 3 (0.5 microg) reduced aggression but not pup retrieval. c-Fos levels were elevated by intracerebroventricular injections of Ucn 1 (0.2 microg) and Ucn 3 (0.5 microg) in 2 and 6 brain regions, respectively; however, both triggered increases in bed nucleus of the stria terminalis dorsal (BNSTd) and lateral septum (LS). These findings suggest that CRF-related peptides similarly modulate maternal aggression and that BNSTd/LS may be critical sites for negative regulation of maternal aggression.

Aggression↗

PubMed2005

Current models and future directions for understanding the neural circuitries of maternal behaviors in rodents.

Maternal behaviors in rodents include a number of subcomponents, such as nursing, nest building, licking and grooming of pups, pup retrieval, and maternal aggression. Because each behavior involves a unique motor pattern, a unique ensemble neural circuitry must underlie each behavior. To what extent there is overlap in terms of brain regions and specific neurons for each circuit is being actively investigated. This review will first examine overlapping and separate components of pup retrieval and maternal aggression circuitries while examining a central role for medial preoptic area (MPA) in both behaviors. With an emphasis on experimental approaches, the review will then highlight recent findings and propose future directions for understanding maternal behavior regulation. Finally, examples for why studying the neural basis of maternal behaviors can bring insights to other areas of neuroscience, such as feeding, addiction, and anxiety and aggression regulation will be provided.

Aggression↗

PubMed2004

Elevated stress sensitivity in corticotropin-releasing factor receptor 2 deficient mice decreases maternal, but not intermale aggression.

Maternal aggression is a form of aggression towards intruders by lactating females that is critical for defense of offspring. During lactation, fear and anxiety are reduced, the CNS is less responsive to the anxiogenic neuropeptide, corticotropin-releasing factor (CRF), and central injections of CRF inhibit maternal aggression. Together, these previous findings suggest that decreased CRF neurotransmission during lactation supports normal maternal aggression expression. Recent work indicates that mice deficient in CRF receptor 2 (CRFR2) display increased anxiety-like behaviors, have a hypersensitive stress response, and overproduce CRF. In this study, we examined both maternal and intermale aggression in wild-type (WT) and CRFR2-deficient mice. CRFR2-mutant mice exhibited significant deficits in maternal aggression on postpartum Day 4 relative to WT mice in terms of percentage displaying aggression, mean number of attacks, and mean time in aggressive encounters. However, time sniffing male intruder, pup retrieval, number of pups, and performance on the elevated plus maze were similar between genotypes. In contrast, intermale aggression did not differ between genotype in any measure on any of three consecutive test days. For neither form of aggression did sites of attacks on the intruder differ between genotype. Taken together, the results suggest that differences in stress sensitivity and the overproduction of CRF of the knockout (KO) mice specifically affects maternal, but not intermale aggression.

Aggression↗

PubMed2004

Opioid-mediated pain sensitivity in mice bred for high voluntary wheel running.

We tested the hypothesis that thermal tail-flick latency, a common measure of pain sensitivity in rodents, would be altered in lines of mice that had been selectively bred for high voluntary wheel-running behavior. Specifically, we predicted that the selected (High-Runner) lines would show decreased pain sensitivity relative to their control (C; randombred) lines, and would respond differently to drugs that block opioid receptors. We first compared tail-flick latency between High-Runner and C female mice during the day (no wheel access) and at night (with wheel access). Second, we compared effects of the opioid antagonist naloxone (10 mg/kg, i.p.) on tail-flick latency during the day (no wheel access). Third, we compared effects of naloxone (5 and 10 mg/kg, i.p.) and naltrexone, a longer-lasting opioid antagonist (0.1, 1, 5, 10, 50, and 100 mg/kg, i.p.), on voluntary wheel running. Tail-flick latencies were longer at night (when mice were active on wheels), but mice from High-Runner and C lines did not differ during the day or night. Administration of naloxone (10 mg/kg, i.p.) decreased tail-flick latency measured during the day, equally in High-Runner and C mice. Naloxone (5 and 10 mg/kg, i.p.) and high doses of naltrexone (50 and 100 mg/kg, i.p.) decreased wheel running equally in High-Runner and C mice. Further studies will be required to determine whether other types of pain sensitivity have also failed to evolve in association with increased voluntary wheel running.

Analysis of Variance↗

PubMed2004

L-citrulline immunoreactivity reveals nitric oxide production in the electromotor and electrosensory systems of the weakly electric fish, Apteronotus leptorhynchus.

Weakly electric fish produce electric organ discharges (EODs) used for electrolocation and communication. In the brown ghost knifefish, Apteronotus leptorhynchus, several neuron types in brain regions that control the EOD or process electrosensory information express nitric oxide synthase (NOS). The present study used immunoreactivity for L-citrulline, a byproduct of the production of nitric oxide (NO) by NOS, to assess NO production in NOS-expressing neurons. A polyclonal antibody against L-citrulline produced specific labeling in most neuronal populations previously identified to express NOS. Specifically, several cell types that precisely encode temporal information and/or fire at high frequencies, including spherical cells in the electrosensory lateral line lobe, giant cells in layer VI of the dorsal torus semicircularis, and pacemaker and relay cells in the pacemaker nucleus, were strongly immunoreactive for L-citrulline. This suggests that these neurons produced high levels of NO. Notably, electromotor neurons, which also strongly express NOS, were not immunoreactive for L-citrulline, suggesting that NOS did not produce high levels of NO in these neurons. No apparent differences in L-citrulline distribution or intensity were observed between socially isolated fish and fish exposed to playback stimuli simulating the presence of a conspecific. This suggests that social stimulation by electrocommunication signals is not necessary for high levels of NO production in many NOS-positive neurons. Future studies focusing on regulation of NO production in these systems, and the effects of NO on electrosensory processing and electromotor pattern generation will help elucidate the function of NO signaling pathways in this system.

Animals↗

PubMed2004

Diurnal levels of Fos immunoreactivity are elevated within hypocretin neurons in lactating mice.

The hypocretins modulate arousal via actions across multiple terminal fields. Thus, alterations in hypocretin neurotransmission may contribute to altered sleep patterns observed during lactation. This study examined whether lactation is associated with alterations in the number of hypocretin neurons and in diurnal Fos-immunoreactivity within hypocretin neurons in female mice. Alterations in Fos-immunoreactivity were also examined within two hypocretin terminal regions; the medial preoptic area and the locus coeruleus. Fos-immunoreactivity was increased within hypocretin neurons and the medial preoptic area in lactating females. No differences were observed in the number of hypocretin neurons or in Fos-immunoreactivity within the locus coeruleus.

Animals↗

PubMed2004

Corticotropin-releasing factor inhibits maternal aggression in mice.

Lactating females that fiercely protect offspring exhibit decreased fear and anxiety. The authors tested whether decreased corticotropin-releasing factor (CRF), an activator of fear and anxiety, plays a functional role in maternal aggression. Intracerebroventricular (icv) injections of CRF (1.0 and 0.2 microg, but not 0.02 microg) significantly inhibited maternal aggression but not other maternal behaviors. The CRF antagonist D-Phe-CRF(12-41) had no effect. Maternal aggression and icv CRF (0.2 microg) induced Fos in 11 of the same regions, including the lateral and medial septum, the bed nucleus of the stria terminalis, the medial and central amygdala, the periaqueductal gray, the dorsal raphe, and the locus coeruleus. These findings suggest that decreased CRF is necessary for maternal aggression and may act by altering brain activity in response to an intruder.

Aggression↗

PubMed2003

Predatory aggression, but not maternal or intermale aggression, is associated with high voluntary wheel-running behavior in mice.

Predatory (towards crickets), intermale, and maternal aggression were examined in four replicate lines of mice that had been selectively bred for high wheel-running (S) and in four random-bred control lines (C). In generation 18, individual differences in both predatory and intermale aggression were significantly consistent across four trial days, but predatory and intermale aggression were uncorrelated both at the individual level and among the eight line means. Latencies to attack crickets were significantly lower in S lines as a group. Intermale aggression, however, did not differ between S and C lines. S lines were significantly smaller in body mass, but did not differ in either testes mass or plasma testosterone. In generations 28 and 30, respectively, S and C lines did not differ in either maternal or intermale aggression. However, significant differences among the individual lines were found for maternal aggression, and one S line exhibited an extremely high mean time of aggression (>120 sec for a 5-min test). Maternal and intermale aggression were not correlated among the eight line means or at the level of individual variation. Overall, our results suggest: (1) predatory aggression and voluntary wheel-running are positively related at the genetic level; (2) predatory and intermale aggression are unrelated at a genetic level; and (3) maternal and intermale aggression are not tightly related at the genetic level. Possible relationships between predatory aggression, dopamine, and wheel-running behavior are discussed.

Aggression↗

PubMed2003

Patterns of brain activity associated with variation in voluntary wheel-running behavior.

Rodents spontaneously run on wheels, but what underlies variation within and between species is unknown. This study used Fos immunoreactivity to compare brain activity in mice selectively bred for high wheel running (S) versus control (C) mice. Mice ran for 6 days, but on Day 7, half the mice were prevented from running. A strong positive correlation was found between running distance and Fos in the dentate gyrus of C runners that was lost in S runners. In mice prevented from running, Fos was higher in S than in C in the lateral hypothalamus, medial frontal cortex, and striatum. Results implicate specific brain regions in motivation to run and others in control of the intensity of the locomotor behavior itself.

Analysis of Variance↗

PubMed2002

Sensory, hormonal, and neural control of maternal aggression in laboratory rodents.

Parental animals of many rodent species display fierce and persistent aggression toward unfamiliar conspecifics that appears to protect their often altricial and defenseless young. We herein review studies of the sensory, hormonal, neuroanatomical, and neurochemical mechanisms underlying maternal aggression in laboratory rodents. The relationship between maternal aggression and fearfulness or anxiety is also discussed.

Aggression↗