Doctor of Philosophy, University Of Bristol (2009)
Bachelor of Arts, Bowdoin College (2001)
Mehrdad Shamloo, Postdoctoral Faculty Sponsor
- Toxoplasma gondii Is Dependent on Glutamine and Alters Migratory Profile of Infected Host Bone Marrow Derived Immune Cells through SNAT2 and CXCR4 Pathways PLOS ONE 2014; 9 (10)
Patterns of Toxoplasma gondii cyst distribution in the forebrain associate with individual variation in predator odor avoidance and anxiety-related behavior in male Long-Evans rats
BRAIN BEHAVIOR AND IMMUNITY
2014; 37: 122-133
Toxoplasma gondii (T. gondii) is one of the world's most successful brain parasites. T. gondii engages in parasite manipulation of host behavior and infection has been epidemiologically linked to numerous psychiatric disorders. Mechanisms by which T. gondii alters host behavior are not well understood, but neuroanatomical cyst presence and the localized host immune response to cysts are potential candidates. The aim of these studies was to test the hypothesis that T. gondii manipulation of specific host behaviors is dependent on neuroanatomical location of cysts in a time-dependent function post-infection. We examined neuroanatomical cyst distribution (53 forebrain regions) in infected rats after predator odor aversion behavior and anxiety-related behavior in the elevated plus maze and open field arena, across a 6-week time course. In addition, we examined evidence for microglial response to the parasite across the time course. Our findings demonstrate that while cysts are randomly distributed throughout the forebrain, individual variation in cyst localization, beginning 3weeks post-infection, can explain individual variation in the effects of T. gondii on behavior. Additionally, not all infected rats develop cysts in the forebrain, and attenuation of predator odor aversion and changes in anxiety-related behavior are linked with cyst presence in specific forebrain areas. Finally, the immune response to cysts is striking. These data provide the foundation for testing hypotheses about proximate mechanisms by which T. gondii alters behavior in specific brain regions, including consequences of establishment of a homeostasis between T. gondii and the host immune response.
View details for DOI 10.1016/j.bbi.2013.11.012
View details for Web of Science ID 000333071000015
View details for PubMedID 24269877
Uncontrollable, But Not Controllable, Stress Desensitizes 5-HT1A Receptors in the Dorsal Raphe Nucleus
JOURNAL OF NEUROSCIENCE
2011; 31 (40): 14107-14115
Uncontrollable stressors produce behavioral changes that do not occur if the organism can exercise behavioral control over the stressor. Previous studies suggest that the behavioral consequences of uncontrollable stress depend on hypersensitivity of serotonergic neurons in the dorsal raphe nucleus (DRN), but the mechanisms involved have not been determined. We used ex vivo single-unit recording in rats to test the hypothesis that the effects of uncontrollable stress are produced by desensitization of DRN 5-HT(1A) autoreceptors. These studies revealed that uncontrollable, but not controllable, tail shock impaired 5-HT(1A) receptor-mediated inhibition of DRN neuronal firing. Moreover, this effect was observed only at time points when the behavioral effects of uncontrollable stress are present. Furthermore, temporary inactivation of the medial prefrontal cortex with the GABA(A) receptor agonist muscimol, which eliminates the protective effects of control on behavior, led even controllable stress to now produce functional desensitization of DRN 5-HT(1A) receptors. Additionally, behavioral immunization, an experience with controllable stress before uncontrollable stress that prevents the behavioral outcomes of uncontrollable stress, also blocked functional desensitization of DRN 5-HT(1A) receptors by uncontrollable stress. Last, Western blot analysis revealed that uncontrollable stress leads to desensitization rather than downregulation of DRN 5-HT(1A) receptors. Thus, treatments that prevent controllable stress from being protective led to desensitization of 5-HT(1A) receptors, whereas treatments that block the behavioral effects of uncontrollable stress also blocked 5-HT(1A) receptor desensitization. These data suggest that uncontrollable stressors produce a desensitization of DRN 5-HT(1A) autoreceptors and that this desensitization is responsible for the behavioral consequences of uncontrollable stress.
View details for DOI 10.1523/JNEUROSCI.3095-11.2011
View details for Web of Science ID 000295805500007
View details for PubMedID 21976495
INVESTIGATION OF A CENTRAL NUCLEUS OF THE AMYGDALA/DORSAL RAPHE NUCLEUS SEROTONERGIC CIRCUIT IMPLICATED IN FEAR-POTENTIATED STARTLE
2011; 179: 104-119
Serotonergic systems are thought to play an important role in control of motor activity and emotional states. We used a fear-potentiated startle paradigm to investigate the effects of a motor-eliciting stimulus in the presence or absence of induction of an acute fear state on serotonergic neurons in the dorsal raphe nucleus (DR) and cells in subdivisions of the central amygdaloid nucleus (CE), a structure that plays an important role in fear responses, using induction of the protein product of the immediate-early gene, c-Fos. In Experiment 1 we investigated the effects of fear conditioning training, by training rats to associate a light cue (conditioned stimulus, CS; 1000 lx, 2 s) with foot shock (0.5 s, 0.5 mA) in a single session. In Experiment 2 rats were given two training sessions identical to Experiment 1 on days 1 and 2, then tested in one of four conditions on day 3: (1) placement in the training context without exposure to either the CS or acoustic startle (AS), (2) exposure to 10 trials of the 2 s CS, (3) exposure to 40 110 dB AS trials, or (4) exposure to 40 110 dB AS trials with 10 of the trials preceded by and co-terminating with the CS. All treatments were conducted during a 20 min session. Fear conditioning training, by itself, increased c-Fos expression in multiple subdivisions of the CE and throughout the DR. In contrast, fear-potentiated startle selectively increased c-Fos expression in the medial subdivision of the CE and in serotonergic neurons in the dorsal part of the dorsal raphe nucleus (DRD). These data are consistent with previous studies demonstrating that fear-related stimuli selectively activate DRD serotonergic neurons. Further studies of this mesolimbocortical serotonergic system could have important implications for understanding mechanisms underlying vulnerability to stress-related psychiatric disorders, including anxiety and affective disorders.
View details for DOI 10.1016/j.neuroscience.2011.01.042
View details for Web of Science ID 000288842400011
View details for PubMedID 21277950
Evidence for in vivo thermosensitivity of serotonergic neurons in the rat dorsal raphe nucleus and raphe pallidus nucleus implicated in thermoregulatory cooling
2011; 227 (2): 264-278
The ability to sense and respond appropriately to increases in ambient and body temperatures is critical for the survival of all animals. Although evidence suggests that brain serotonergic systems play a role in thermoregulation, including thermoregulatory cooling, evidence for activation of brainstem serotonergic neurons in vivo, in unanesthetized animals, during heat exposure is lacking. In this experiment we tested the hypothesis that populations of serotonergic neurons in the midbrain and medullary raphe complex are activated following exposure to warm ambient temperature. Rats were exposed to an incubation chamber at either warm ambient temperature (37°C) or room temperature (RT; 23°C) for 105 min. Brains then were removed and processed for immunohistochemical detection of the protein product of the immediate-early gene c-fos (as a marker of neuronal activation) and tryptophan hydroxylase (as a marker of serotonergic neurons). Exposure to warm ambient temperature increased body temperature and c-Fos expression in topographically organized populations of serotonergic neurons in the dorsal raphe nucleus. Activation of the dorsal raphe nucleus serotonergic system was positively correlated with body temperature following exposure to the incubation chamber. In the medulla, exposure to warm ambient temperature, compared with exposure to RT, decreased c-Fos expression in serotonergic neurons in the raphe pallidus nucleus and in non-serotonergic cells in the rostral ventrolateral medulla. Together, these results provide evidence for multiple but anatomically discrete thermosensitive serotonergic systems that may have implications for the regulation of body temperature, as well as, via projections to forebrain targets, cognitive and affective functions.
View details for DOI 10.1016/j.expneurol.2010.11.012
View details for Web of Science ID 000286714900003
View details for PubMedID 21111735
A triple urocortin knockout mouse model reveals an essential role for urocortins in stress recovery
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
2010; 107 (44): 19020-19025
Responding to stressful events requires numerous adaptive actions involving integrated changes in the central nervous and neuroendocrine systems. Numerous studies have implicated dysregulation of stress-response mechanisms in the etiology of stress-induced psychopathophysiologies. The urocortin neuropeptides are members of the corticotropin-releasing factor family and are associated with the central stress response. In the current study, a triple-knockout (tKO) mouse model lacking all three urocortin genes was generated. Intriguingly, these urocortin tKO mice exhibit increased anxiety-like behaviors 24 h following stress exposure but not under unstressed conditions or immediately following exposure to acute stress. The inability of these mutants to recover properly from the exposure to an acute stress was associated with robust alterations in the expression profile of amygdalar genes and with dysregulated serotonergic function in stress-related neurocircuits. These findings position the urocortins as essential factors in the stress-recovery process and suggest the tKO mouse line as a useful stress-sensitive mouse model.
View details for DOI 10.1073/pnas.1013761107
View details for Web of Science ID 000283749000052
View details for PubMedID 20937857
Urocortin-1 and-2 double-deficient mice show robust anxiolytic phenotype and modified serotonergic activity in anxiety circuits
2010; 15 (4): 426-441
The urocortin (Ucn) family of neuropeptides is suggested to be involved in homeostatic coping mechanisms of the central stress response through the activation of corticotropin-releasing factor receptor type 2 (CRFR2). The neuropeptides, Ucn1 and Ucn2, serve as endogenous ligands for the CRFR2, which is highly expressed by the dorsal raphe serotonergic neurons and is suggested to be involved in regulating major component of the central stress response. Here, we describe genetically modified mice in which both Ucn1 and Ucn2 are developmentally deleted. The double knockout mice showed a robust anxiolytic phenotype and altered hypothalamic-pituitary-adrenal axis activity compared with wild-type mice. The significant reduction in anxiety-like behavior observed in these mice was further enhanced after exposure to acute stress, and was correlated with the levels of serotonin and 5-hydroxyindoleacetic acid measured in brain regions associated with anxiety circuits. Thus, we propose that the Ucn/CRFR2 serotonergic system has an important role in regulating homeostatic equilibrium under challenge conditions.
View details for DOI 10.1038/mp.2009.115
View details for Web of Science ID 000275929100011
View details for PubMedID 19884890
Acoustic stimulation in vivo and corticotropin-releasing factor in vitro increase tryptophan hydroxylase activity in the rat caudal dorsal raphe nucleus
2009; 455 (1): 36-41
Exposure of rats to unpredictable loud sound pulses increases activity of the rate-limiting enzyme for serotonin synthesis, tryptophan hydroxylase (TPH), in the median raphe nucleus (MnR) and a mesolimbocortical serotonergic system. Corticotropin-releasing factor (CRF)-induced activation of a subset of serotonergic neurons in the caudal dorsal raphe nucleus (DR) may underlie stress-related increases in TPH activity in the MnR and a mesolimbocortical serotonergic system. An in vivo acoustic stimulation paradigm and an in vitro brain slice preparation were designed to test the hypothesis that stress-related stimuli and CRF receptor activation have convergent actions on TPH activity in the caudal DR (DRC). We measured 5-hydroxytryptophan (5-HTP) accumulation as an index of TPH activity following inhibition of aromatic amino acid decarboxylase (using NSD-1015). To examine effects of acoustic stimulation on TPH activity, male Wistar rats, pretreated with NSD-1015, were exposed to a 30 min sham, predictable or unpredictable acoustic stimulation paradigm; brains were frozen and microdissected for analyses of tissue 5-HTP concentrations in subregions of the DR. To examine the effect of CRF receptor activation on TPH activity, freshly prepared brain slices were exposed to CRF (0-2000 nM) for 10 min in the presence of NSD-1015, then frozen and microdissected for analysis of tissue 5-HTP concentrations. Increases in TPH activity in the DRC, but not other subregions, were observed in both paradigms. These findings are consistent with the hypothesis that stress-related increases in TPH activity are mediated via effects of CRF or CRF-related neuropeptides on a mesolimbocortical serotonergic system originating in the DRC.
View details for DOI 10.1016/j.neulet.2009.03.025
View details for Web of Science ID 000265661900009
View details for PubMedID 19429102
EXPOSURE TO AN OPEN-FIELD ARENA INCREASES c-Fos EXPRESSION IN A SUBPOPULATION OF NEURONS IN THE DORSAL RAPHE NUCLEUS, INCLUDING NEURONS PROJECTING TO THE BASOLATERAL AMYGDALOID COMPLEX
2008; 157 (4): 733-748
Serotonergic systems in the dorsal raphe nucleus are thought to play an important role in the regulation of anxiety states. To investigate responses of neurons in the dorsal raphe nucleus to a mild anxiety-related stimulus, we exposed rats to an open-field, under low-light or high-light conditions. Treatment effects on c-Fos expression in serotonergic and non-serotonergic cells in the midbrain raphe nuclei were determined 2 h following open-field exposure or home cage control (CO) conditions. Rats tested under both light conditions responded with increases in c-Fos expression in serotonergic neurons within subdivisions of the midbrain raphe nuclei compared with CO rats. However, the total numbers of serotonergic neurons involved were small suggesting that exposure to the open-field may affect a subpopulation of serotonergic neurons. To determine if exposure to the open-field activates a subset of neurons in the midbrain raphe complex that projects to forebrain circuits regulating anxiety states, we used cholera toxin B subunit (CTb) as a retrograde tracer to identify neurons projecting to the basolateral amygdaloid complex (BL) in combination with c-Fos immunostaining to identify cells that responded to open-field exposure. Rats received a unilateral injection of CTb into the BL. Seven to 11 days following CTb injection rats were either, 1) exposed to an open-field in low-light conditions, 2) briefly handled or 3) left undisturbed in home cages. Dual immunostaining for c-Fos and CTb revealed an increase in the percentage of c-Fos-immunoreactive BL-projecting neurons in open-field-exposed rats compared with handled and control rats. Dual immunostaining for tryptophan hydroxylase and CTb revealed that a majority (65%) of BL-projecting neurons were serotonergic, leaving open the possibility that activated neurons were serotonergic, non-serotonergic, or both. These data are consistent with the hypothesis that exposure to anxiogenic stimuli activates a subset of neurons in the midbrain raphe complex projecting to amygdala anxiety circuits.
View details for DOI 10.1016/j.neuroscience.2008.09.050
View details for Web of Science ID 000261602700003
View details for PubMedID 18951955
Evidence for serotonin synthesis-dependent regulation of in vitro neuronal firing rates in the midbrain raphe complex
EUROPEAN JOURNAL OF PHARMACOLOGY
2008; 590 (1-3): 136-149
Evidence suggests that 5-hydroxytryptamine 1A (5-HT(1A)) receptor-mediated autoregulation of serotonergic neuronal firing rates is impaired in stress-related neuropsychiatric disorders. In vitro models may provide insight into neural mechanisms underlying regulation of serotonergic systems. However, serotonin synthesis and tonic autoregulation of serotonergic neuronal firing rates are impaired in in vitro preparations lacking tryptophan. We describe the effects of perfusion of living rat brain slices with tryptophan on both 1) tissue concentrations of serotonin metabolites and 2) neuronal firing rates within the dorsal raphe nucleus. Brain slices were perfused with artificial cerebrospinal fluid lacking tryptophan for 4 h, followed by exposure to 1) 40 microM tryptophan (0-60 min) or 2) 0-400 microM tryptophan (23 min) and microdissected for analysis of indole concentrations. Parallel studies examined effects of tryptophan on neuronal firing rates and interactions with drugs expected to alter synaptic concentrations of serotonin. Tryptophan resulted in time-dependent and concentration-dependent increases in serotonin and serotonin metabolites, effects that were correlated with restoration of tonic autoinhibition of dorsal raphe nucleus neuronal firing rates. Inhibition of serotonin synthesis resulted in time-dependent and concentration-dependent increases in 5-hydroxtryptophan that correlated with reversal of the tryptophan-mediated autoinhibition of neuronal firing rates. Tryptophan modulated effects of several drugs on neuronal firing rates, including a selective 5-HT(1A) receptor antagonist (WAY-100635), a monoamine oxidase inhibitor (pargyline), a selective serotonin reuptake inhibitor (fluoxetine), and a serotonin-releasing agent (methylenedioxymethamphetamine). These studies support the hypothesis that tonic autoregulation of serotonergic neuronal firing rates is dependent on tryptophan availability and characterise conditions necessary to study this process in vitro.
View details for DOI 10.1016/j.ejphar.2008.06.014
View details for Web of Science ID 000258712500020
View details for PubMedID 18577382
Serotonergic Systems, Anxiety, and Affective Disorder Focus on the Dorsomedial Part of the Dorsal Raphe Nucleus
STRESS, NEUROTRANSMITTERS, AND HORMONES: NEUROENDOCRINE AND GENETIC MECHANISMS
2008; 1148: 86-94
Depressed suicide patients have elevated expression of neuronal tryptophan hydroxylase 2 (TPH2) mRNA and protein in midbrain serotonergic neurons, as well as increases in brain serotonin turnover. The mechanisms underlying these changes are uncertain, but increased TPH2 expression and serotonin turnover could result from genetic influences, adverse early life experiences, or acute stressful life events, all of which can alter serotonergic neurotransmission and have been implicated in determining vulnerability to major depression. Emerging evidence suggests that there are several different stress-related subsets of serotonergic neurons, each with a unique role in the integrated stress response. Here we review our current understanding of how genetic and environmental factors may influence TPH2 mRNA expression and serotonergic neurotransmission, focusing in particular on the dorsomedial part of the dorsal raphe nucleus. This subdivision of the dorsal raphe nucleus is selectively innervated by key forebrain structures implicated in regulation of anxiety states, it gives rise to projections to a distributed neural system mediating anxiety states, and serotonergic neurons within this subdivision are selectively activated by a number of stress- and anxiety-related stimuli. A better understanding of the anatomical and functional properties of specific stress- or anxiety-related serotonergic systems should aid our understanding of the neural mechanisms underlying the etiology of anxiety and affective disorders.
View details for DOI 10.1196/annals.1410.004
View details for Web of Science ID 000262398300007
View details for PubMedID 19120094
Identification of an immune-responsive mesolimbocortical serotonergic system: Potential role in regulation of emotional behavior
2007; 146 (2): 756-772
Peripheral immune activation can have profound physiological and behavioral effects including induction of fever and sickness behavior. One mechanism through which immune activation or immunomodulation may affect physiology and behavior is via actions on brainstem neuromodulatory systems, such as serotonergic systems. We have found that peripheral immune activation with antigens derived from the nonpathogenic, saprophytic bacterium, Mycobacterium vaccae, activated a specific subset of serotonergic neurons in the interfascicular part of the dorsal raphe nucleus (DRI) of mice, as measured by quantification of c-Fos expression following intratracheal (12 h) or s.c. (6 h) administration of heat-killed, ultrasonically disrupted M. vaccae, or heat-killed, intact M. vaccae, respectively. These effects were apparent after immune activation by M. vaccae or its components but not by ovalbumin, which induces a qualitatively different immune response. The effects of immune activation were associated with increases in serotonin metabolism within the ventromedial prefrontal cortex, consistent with an effect of immune activation on mesolimbocortical serotonergic systems. The effects of M. vaccae administration on serotonergic systems were temporally associated with reductions in immobility in the forced swim test, consistent with the hypothesis that the stimulation of mesolimbocortical serotonergic systems by peripheral immune activation alters stress-related emotional behavior. These findings suggest that the immune-responsive subpopulation of serotonergic neurons in the DRI is likely to play an important role in the neural mechanisms underlying regulation of the physiological and pathophysiological responses to both acute and chronic immune activation, including regulation of mood during health and disease states. Together with previous studies, these findings also raise the possibility that immune stimulation activates a functionally and anatomically distinct subset of serotonergic neurons, different from the subset of serotonergic neurons activated by anxiogenic stimuli or uncontrollable stressors. Consequently, selective activation of specific subsets of serotonergic neurons may have distinct behavioral outcomes.
View details for DOI 10.1016/j.neuroscience.2007.01.067
View details for Web of Science ID 000246535000026
View details for PubMedID 17367941
Pharmacology of the beta-carboline FG-7142, a partial inverse agonist at the benzodiazepine allosteric site of the GABA(A) receptor: Neurochemical, neurophysiological, and behavioral effects
CNS DRUG REVIEWS
2007; 13 (4): 475-501
Given the well-established role of benzodiazepines in treating anxiety disorders, beta-carbolines, spanning a spectrum from full agonists to full inverse agonists at the benzodiazepine allosteric site for the GABA(A) receptor, can provide valuable insight into the neural mechanisms underlying anxiety-related physiology and behavior. FG-7,142 is a partial inverse agonist at the benzodiazepine allosteric site with its highest affinity for the alpha1 subunit-containing GABA(A) receptor, although it is not selective. FG-7,142 also has its highest efficacy for modulation of GABA-induced chloride flux mediated at the alpha1 subunit-containing GABA(A) receptor. FG-7,142 activates a recognized anxiety-related neural network and interacts with serotonergic, dopaminergic, cholinergic, and noradrenergic modulatory systems within that network. FG-7,142 has been shown to induce anxiety-related behavioral and physiological responses in a variety of experimental paradigms across numerous mammalian and non-mammalian species, including humans. FG-7,142 has proconflict actions across anxiety-related behavioral paradigms, modulates attentional processes, and increases cardioacceleratory sympathetic reactivity and neuroendocrine reactivity. Both acute and chronic FG-7,142 treatment are proconvulsive, upregulate cortical adrenoreceptors, decrease subsequent actions of GABA and beta-carboline agonists, and increase the effectiveness of subsequent GABA(A) receptor antagonists and beta-carboline inverse agonists. FG-7,142, as a partial inverse agonist, can help to elucidate individual components of full agonism of benzodiazepine binding sites and may serve to identify the specific GABA(A) receptor subtypes involved in specific behavioral and physiological responses.
View details for Web of Science ID 000251503700006
View details for PubMedID 18078430
Lipopolysaccharide has indomethacin-sensitive actions on Fos expression in topographically organized subpopulations of serotonergic neurons
BRAIN BEHAVIOR AND IMMUNITY
2006; 20 (6): 569-577
Peripheral immune activation results in physiological and behavioral responses including changes in the level of behavioral arousal. One mechanism through which immune activation can influence these responses is via actions on brainstem neuromodulatory systems, including serotonergic systems. To investigate the effects of peripheral immune activation on serotonergic systems and behavior, and the potential role of prostanoids in mediating these effects, we compared the effects of intraperitoneal injections of lipopolysaccharide (LPS), in the presence or absence of the cyclooxygenase inhibitor indomethacin, on total plasma L-tryptophan concentrations, Fos expression in subdivisions of the brainstem raphe complex, and home cage behaviors. Peripheral LPS administration had no effect on total plasma L-tryptophan concentrations but increased Fos expression in serotonergic neurons selectively within the interfascicular (DRI) and ventrolateral (DRVL) subdivisions of the dorsal raphe nucleus 4 h following treatment; pretreatment with indomethacin blocked the LPS-induced increases in Fos expression within the DRI and DRVL. Peripheral LPS administration decreased measures of behavioral arousal including locomotion, rearing, climbing, and self-grooming; LPS administration had no effect on these behaviors in mice pretreated with indomethacin. The indomethacin-sensitive effects of LPS on Fos expression in the DRI may be due to selective activation of Type II serotonergic neurons which are largely restricted to the DRI region and have unique afferent regulatory mechanisms and behavioral correlates. Further studies of the effects of peripheral immune activation on DRI serotonergic systems may lead to a better understanding of the relationships among immune function, serotonergic systems, and behavior.
View details for DOI 10.1016/j.bbi.2006.01.006
View details for Web of Science ID 000241793800009
View details for PubMedID 16554144
Neuropeptide binding reflects convergent and divergent evolution in species-typical group sizes
HORMONES AND BEHAVIOR
2006; 50 (2): 223-236
Neuroendocrine factors that produce species differences in aggregation behavior ("sociality") are largely unknown, although relevant studies should yield important insights into mechanisms of affiliation and social evolution. We here focused on five species in the avian family Estrildidae that differ selectively in their species-typical group sizes (all species are monogamous and occupy similar habitats). These include two highly gregarious species that independently evolved coloniality; two territorial species that independently evolved territoriality; and an intermediate, modestly gregarious species that is a sympatric congener of one of the territorial species. Using males and females of each species, we examined binding sites for (125)I-vasoactive intestinal polypeptide (VIP), (125)I-sauvagine (SG; a ligand for corticotropin releasing factor, CRF, receptors) and a linear (125)I-V(1a) vasopressin antagonist (to localize receptors for vasotocin, VT). VIP, CRF and VT are neuropeptides that influence stress, anxiety and/or various social behaviors. For numerous areas (particularly within the septal complex), binding densities in the territorial species differed significantly from binding in the more gregarious species, and in most of these cases, binding densities for the moderately gregarious species were either comparable to the two colonial species or were intermediate to the territorial and colonial species. Such patterns were observed for (125)I-VIP binding in the medial bed nucleus of the stria terminalis, medial septum, septohippocampal septum, and subpallial zones of the lateral septum; for (125)I-SG binding in the infundibular hypothalamus, and lateral and medial divisions of the ventromedial hypothalamus; and for the linear (125)I-V(1a) antagonist in the medial septum, and the pallial and subpallial zones of the caudal lateral septum. With the exception of (125)I-SG binding in the infundibular hypothalamus, binding densitites are positively related to sociality.
View details for DOI 10.1016/j.yhbeh.2006.03.005
View details for Web of Science ID 000239179200007
View details for PubMedID 16643915
The anxiogenic drug FG-7142 increases serotonin metabolism in the rat medial prefrontal cortex
PHARMACOLOGY BIOCHEMISTRY AND BEHAVIOR
2006; 84 (2): 266-274
The neural mechanisms underlying anxiety states are believed to involve interactions among forebrain limbic circuits and brainstem serotonergic systems. Consistent with this hypothesis, FG-7142, a partial inverse agonist at the benzodiazepine allosteric site of the GABAA receptor, increases c-Fos expression within a subpopulation of brainstem serotonergic neurons. Paradoxically, FG-7142 has no effect on extracellular serotonin concentrations, as measured using in vivo microdialysis, in certain anxiety-related brain structures. This study tested the hypothesis that FG-7142 alters serotonin metabolism within one or more nodes of a defined anxiety-related forebrain circuit. Rats received one of four treatments (vehicle, 1.9, 3.8, or 7.5 mg/kg FG-7142, i.p.) and brains were collected 1 h following treatment. Thirteen forebrain regions were microdissected and analyzed for l-tryptophan, serotonin, and 5-hydroxyindoleacetic acid concentrations using high pressure liquid chromatography with electrochemical detection. FG-7142 (7.5 mg/kg) increased l-tryptophan, serotonin, and 5-hydroxyindoleacetic acid concentrations in the prelimbic cortex but not in several other regions studied including subdivisions of the amygdala and bed nucleus of the stria terminalis. These data demonstrate that FG-7142 alters brain tryptophan concentrations and serotonin metabolism in specific components of an anxiety-related forebrain circuit including the medial prefrontal cortex, an important structure involved in executive function and the regulation of emotional behavior.
View details for DOI 10.1016/j.pbb.2006.05.007
View details for Web of Science ID 000239856400011
View details for PubMedID 16784772
Evidence supporting a role for corticotropin-releasing factor type 2 (CRF2) receptors in the regulation of subpopulations of serotonergic neurons
2006; 1070 (1): 77-89
Corticotropin-releasing factor (CRF)-related peptides can modulate stress-related physiology and behavior. Some of these effects may be mediated via the CRF type 2 (CRF2) receptor on serotonergic neurons in the dorsal raphe nucleus (DR). To determine if the CRF2 receptor agonist urocortin 2 (Ucn 2) increases c-Fos expression in rat DR serotonergic neurons via actions on CRF2 receptors, we gave intracerebroventricular (icv) injections of mouse Ucn 2 after icv injections of either saline or the CRF2 receptor antagonist antisauvagine-30 (ASV-30). Double immunostaining methods for c-Fos and tryptophan hydroxylase revealed that, consistent with previous studies, mouse Ucn 2 increased c-Fos expression in tryptophan hydroxylase immunostained neurons in the middle and caudal parts (-8.18, -8.54, and -9.16 mm bregma) of the dorsal subdivision of the dorsal raphe nucleus 2 h after drug treatment. Pre-treatment with ASV-30 blocked these effects. Mouse Ucn 2 had no effect on c-Fos expression within the median raphe nucleus, consistent with the hypothesis that Ucn 2 has specific actions on an anatomically and functionally distinct subset of serotonergic neurons via activation of CRF2 receptors. These findings are also consistent with the hypothesis that Ucn 2, or another CRF-related neuropeptide acting at CRF2 receptors, modulates physiological and behavioral responses to stress-related stimuli via actions on a specific subset of serotonergic neurons within the dorsal raphe nucleus.
View details for DOI 10.1016/j.brainres.2005.10.096
View details for Web of Science ID 000236099000010
View details for PubMedID 16403469
Tryptophan metabolism in the central nervous system: medical implications.
Expert reviews in molecular medicine
2006; 8 (20): 1-27
The metabolism of the amino acid L-tryptophan is a highly regulated physiological process leading to the generation of several neuroactive compounds within the central nervous system. These include the aminergic neurotransmitter serotonin (5-hydroxytryptamine, 5-HT), products of the kynurenine pathway of tryptophan metabolism (including 3-hydroxykynurenine, 3-hydroxyanthranilic acid, quinolinic acid and kynurenic acid), the neurohormone melatonin, several neuroactive kynuramine metabolites of melatonin, and the trace amine tryptamine. The integral role of central serotonergic systems in the modulation of physiology and behaviour has been well documented since the first description of serotonergic neurons in the brain some 40 years ago. However, while the significance of the peripheral kynurenine pathway of tryptophan metabolism has also been recognised for several decades, it has only recently been appreciated that the synthesis of kynurenines within the central nervous system has important consequences for physiology and behaviour. Altered kynurenine metabolism has been implicated in the pathophysiology of conditions such as acquired immunodeficiency syndrome (AIDS)-related dementia, Huntington's disease and Alzheimer's disease. In this review we discuss the molecular mechanisms involved in regulating the metabolism of tryptophan and consider the medical implications associated with dysregulation of both serotonergic and kynurenine pathways of tryptophan metabolism.
View details for PubMedID 16942634
Neural responses to aggressive challenge correlate with behavior in nonbreeding sparrows
2005; 16 (15): 1719-1723
The present study was conducted on captive male song sparrows (Melospiza melodia) during the nonbreeding season in order to (1) examine Fos and Zenk responses of basal forebrain sites to simulated territorial intrusion and (2) determine how those responses relate to aggression. Numerous forebrain areas showed significant Fos and Zenk responses to simulated territorial intrusion, and in several areas of the hypothalamus and lateral septum, these responses were negatively correlated with aggressive behavior. Homologous areas in mammals show greater responses in subordinate subjects than in dominant subjects. Thus, these brain areas may be responsive to social stressors across a wide range of vertebrates.
View details for Web of Science ID 000233073900022
View details for PubMedID 16189485
Neuro-evolutionary patterning of sociality
PROCEEDINGS OF THE ROYAL SOCIETY B-BIOLOGICAL SCIENCES
2005; 272 (1560): 227-235
Evolutionary shifts in species-typical group size ('sociality') probably reflect natural selection on motivational processes such as social arousal, approach-avoidance, reward, stress/anxiety and dominance. Using four songbird species that differ selectively in sociality (one territorial, one modestly gregarious, and two highly gregarious species), we here examined immediate early gene (IEG) responses of relevant brain regions following exposure to a same-sex conspecific. The paradigm limited behavioural performance, thus species differences should reflect divergence in motivational and/or perceptual processes. Within the extended medial amygdala (which is involved in appetitive approach, social arousal and avoidance), we observed species differences in IEG response that are negatively graded in relation to sociality. In addition, brain areas that are involved in social stress and dominance-related behaviour (ventrolateral septum, anterior hypothalamus and lateral subdivision of the ventromedial hypothalamus) exhibited IEG responses that dichotomously distinguish the territorial species from the three gregarious species. The IEG responses of areas involved in reward (nucleus accumbens and ventral pallidum) and general stress processes (e.g. paraventricular hypothalamus, lateral bed nucleus of the stria terminalis and most areas of the lateral septum) do not correlate with sociality, indicating that social evolution has been accompanied by selection on a relatively discrete suite of motivational systems.
View details for DOI 10.1098/rspb.2004.2892
View details for Web of Science ID 000227616600002
View details for PubMedID 15705546
Neural responses to territorial challenge and nonsocial stress in male song sparrows: segregation, integration, and modulation by a vasopressin V-1 antagonist
HORMONES AND BEHAVIOR
2004; 46 (4): 371-381
The present experiments were conducted to determine (1) which basal forebrain regions and/or their peptidergic components are responsive to social challenge and nonsocial stress, and (2) the influence of an arginine vasopressin V(1) antagonist (AVPa) on these responses. Experiments were conducted in wild-caught male song sparrows (Melospiza melodia) that were housed on seminatural territories (field-based flight cages). Subjects were each fitted with a chronic guide cannula directed at the lateral ventricle and exposed to one of five conditions before sacrifice and histochemistry: saline + simulated territorial intrusion (STI; consisting of song playback and presentation of a caged conspecific male), AVPa + STI, saline + empty cage, AVPa + empty cage, unhandled. Two tissue series were prepared and immunofluorescently double-labeled for ZENK (egr-1) protein and either arginine vasotocin (AVT; avian homologue of AVP) or corticotropin releasing factor (CRF). The results indicate that the neuronal populations that are sensitive to nonsocial stress (capture, handling and infusion) and STI are at least partially segregated. Increases in ZENK-immunoreactive (-ir) nuclei following handling and infusion were observed in a large number of areas, whereas neural responses that were specific to STI were more limited. However, multiple areas showed responses to both handling and STI. AVPa infusions significantly reduced or eliminated most experimental increases in ZENK-ir, suggesting a broad role for endogenous AVT in the modulation of baseline activity and/or stress responsivity, and a much more limited role in the specific response to social challenge. Particular attention is given to the numerous zones of the lateral septum (LS), which are differentially responsive to handling, STI, and V(1)-like receptor blockade. These data suggest that septal AVT modulates neural responses to general stressors, not social stimuli specifically. Thus, species differences in septal AVT function (as previously described in songbirds) likely reflect differences in the relationship of stress or anxiety to species-specific behaviors, or to behavior in species-typical contexts.
View details for DOI 10.1016/j.yhbeh.2004.02.008
View details for Web of Science ID 000224634900001
View details for PubMedID 15465522
Chemoarchitectonic subdivisions of the songbird septum and a comparative overview of septum chemical anatomy in jawed vertebrates
JOURNAL OF COMPARATIVE NEUROLOGY
2004; 473 (3): 293-314
Available data demonstrate that the avian septal region shares a number of social behavior functions and neurochemical features in common with mammals. However, the structural and functional subdivisions of the avian septum remain largely unexplored. In order to delineate chemoarchitectural zones of the avian septum, we prepared a large dataset of double-, triple-, and quadruple-labeled material in a variety of songbird species (finches and waxbills of the family Estrildidae and a limited number of emberizid sparrows) using antibodies against 10 neuropeptides and enzymes. Ten septal zones were identified that were placed into lateral, medial, caudocentral, and septohippocampal divisions, with the lateral and medial divisions each containing multiple zones. The distributions of numerous immunoreactive substances in the lateral septum closely match those of mammals (i.e., distributions of met-enkephalin, vasotocin, galanin, calcitonin gene-related peptide, tyrosine hydroxylase, vasoactive intestinal polypeptide, substance P, corticotropin-releasing factor, and neuropeptide Y), enabling detailed comparisons with numerous chemoarchitectonic zones of the mammalian lateral septum. Our septohippocampal and caudocentral divisions are topographically comparable to the mammalian septohippocampal and septofimbrial nuclei, respectively, although additional data will be required to establish homology. The present data also demonstrate the presence of a medial septal nucleus that is histochemically comparable to the medial septum of mammals. The avian medial septum is clearly defined by peptidergic markers and choline acetyltransferase immunoreactivity. These findings should provide a useful framework for functional and comparative studies, as they suggest that many features of the septum are highly conserved across vertebrate taxa.
View details for DOI 10.1002/cne.20061
View details for Web of Science ID 000221225200001
View details for PubMedID 15116393
Putative isotocin distributions in sonic fish: Relation to vasotocin and vocal-acoustic circuitry
JOURNAL OF COMPARATIVE NEUROLOGY
2003; 462 (1): 1-14
Recent neurophysiological evidence in the plainfin midshipman fish (Porichthys notatus) demonstrated that isotocin (IT) and arginine vasotocin (AVT) modulate fictive vocalizations divergently between three reproductive morphs. To provide an anatomical framework for the modulation of vocalization by IT and to foster comparisons with the distributions of the IT homologues mesotocin (MT) and oxytocin (OT) in other vertebrate groups, we describe putative IT distributions in the midshipman and the closely related gulf toadfish, Opsanus beta. Double-label fluorescent histochemistry was used for IT and AVT (by using antibodies for MT, OT, and the mammalian AVT homologue, arginine vasopressin [AVP]). MT/OT-like immunoreactive (MT/OT-lir) cell groups were found in the anterior parvocellular, posterior parvocellular, and magnocellular preoptic nuclei. MT/OT-lir fibers and putative terminals densely innervated the ventral telencephalon and numerous areas in the hypothalamus and brainstem. These distributions included all sites of vocal-acoustic integration recently identified for the forebrain and midbrain and diencephalic components of the ascending auditory pathway. Results were qualitatively comparable across morphs, species, and seasons. In contrast to the widespread distribution of MT/OT-lir, AVP-lir somata, fibers, and putative terminals were almost completely restricted to vocal-acoustic regions. These data parallel previous descriptions of AVT immunoreactivity in these species, although the present methods showed a previously undescribed, seasonally variable AVP-lir cell group in the anterior tuberal hypothalamus, a vocally active site and a component of the ascending auditory pathway. These findings provided anatomic support for the role of IT and AVT in the modulation of vocal behavior at multiple levels of the central vocal-acoustic circuitry.
View details for DOI 10.1002/cne.10679
View details for Web of Science ID 000183518000001
View details for PubMedID 12761820