Transcriptome Analysis Identifies Oncogenic Tissue Remodeling during Progression from Common Nevi to Early Melanoma.

Early detection and treatment of melanoma, the most aggressive skin cancer, improves the median 5-year survival rate of patients from 25% to 99%. Melanoma development involves a stepwise process during which genetic changes drive histologic alterations within nevi and surrounding tissue. Herein, a comprehensive analysis of publicly available gene expression data sets of melanoma, common or congenital nevi (CN), and dysplastic nevi (DN), assessed molecular and genetic pathways leading to early melanoma. The results demonstrate several pathways reflective of ongoing local structural tissue remodeling activity likely involved during the transition from benign to early-stage melanoma. These processes include the gene expression of cancer-associated fibroblasts, collagens, extracellular matrix, and integrins, which assist early melanoma development and the immune surveillance that plays a substantial role at this early stage. Furthermore, genes up-regulated in DN were also overexpressed in melanoma tissue, supporting the notion that DN may serve as a transitional phase toward oncogenesis. CN collected from healthy individuals exhibited different gene signatures compared with histologically benign nevi tissue located adjacent to melanoma (adjacent nevi). Finally, the expression profile of microdissected adjacent nevi tissue was more similar to melanoma compared with CN, revealing the melanoma influence on this annexed tissue.

CorNeat KPro: Ocular Implantation Study in Rabbits.

PURPOSE: The purpose of this study was to evaluate surgical feasibility and long-term integration of the CorNeat Keratoprosthesis (KPro), a novel synthetic cornea, in rabbits. METHODS: The CorNeat KPro is a synthetic corneal implant designed to treat corneal blindness by using a polymeric scaffold for biointegration, consequently assimilating synthetic optics within ocular tissues. Eight New Zealand White rabbits were implanted unilaterally with the CorNeat KPro and observed for 6 months. Animals were regularly monitored by a certified ophthalmologist using slit-lamp biomicroscopy. One animal developed postoperative endophthalmitis and was removed from the study 7 weeks postsurgery. At termination, eyes were enucleated and evaluated histologically to assess local tissue integration and inflammatory response. RESULTS: The surgical procedure was found feasible. The CorNeat KPro integrated into all operated eyes, resulting in a retention rate of 87.5% at the conclusion of the 6-month follow-up period. We observed minimal-to-mild conjunctival and iridial congestion and did not find additional inflammatory indicators, such as anterior chamber fibrin, flare, or cells. The optical element of the device remained clear with zero incidence of retroprosthetic membrane formation. Histopathological evaluation revealed comparable tissue and cellular reaction in all eyes, consisting of the presence of fibroblasts and associated collagen fibrils within the device's skirt component. Some eyes showed a mild foreign body reaction surrounding the skirt. CONCLUSIONS: Clinical and histological findings indicate the integration of the implanted device into the surrounding tissue, evident by the retention rate and the diffuse infiltration of fibroblasts with collagen deposition among the device's fibrils. These data hold promise for clinical application in humans.

Effects of estrus cycle stage on defensive behavior in female Long-Evans hooded rats.

This study investigated the influence of the estrus cycle in mediating cat odor-induced unconditioned and conditioned defensive behaviors in female Long-Evans hooded rats. Unconditioned defensive behaviors were assessed during predatory cue exposure; conditioned defensive behaviors were examined 24 h after threat exposure. Estrus phases were determined by microscopic examination of vaginal smears within 10 min of completing the behavioral tests. Compared to no-odor controls, female rats exposed to cat odor exhibited both unconditioned and conditioned defensive behaviors, including elevated levels of freezing, risk assessment and avoidance. Rats in proestrus and estrus exhibited reduced levels of defensive behavior during the unconditioned test trial compared to subjects in diestrus and metestrus. Specifically, estrus stages characterized by high levels of circulating estrogens and progesterone were associated with reduced immobility (i.e. freezing) and enhanced active defense (i.e. risk assessment), profiles that may enable mate seeking and subsequent reproduction in potentially dangerous or novel environments. These results suggest a specific role for ovarian hormone fluctuations in mediating unconditioned fear- and anxiety-like defensive behaviors during exposure to predatory odors.

Fibroblast growth factor 2 alters the oxytocin receptor in a developmental model of anxiety-like behavior in male rat pups.

We aimed to determine the short-term effects of early-life stress in the form of maternal separation (MS) on anxiety-like behavior in male rat pups. In order to assess anxiety, we measured 40kHz separation-induced ultrasonic vocalizations (USV) on postnatal day (PND) 11. We further aimed to evaluate the potential involvement of two neurochemical systems known to regulate social and anxiety-like behaviors throughout life: oxytocin (OT) and fibroblast growth factor 2 (FGF2). For these purposes, we tested the effects of neonatal administration (on PND1) of an acute dose of FGF2 on USV and its potential interaction with MS. In addition, we validated the anxiolytic effects of OT and measured oxytocin receptor (OTR) gene expression, binding and epigenetic regulation via histone acetylation. Our results show that MS potentiated USV while acute administration of OT and FGF2 attenuated them. Further, we found that both FGF2 and MS increased OTR gene expression and the association of acH3K14 with the OTR promoter in the bed nucleus of the stria terminalis (BNST). Comparable changes, though not as pronounced, were also found for the central amygdala (CeA). Our findings suggest that FGF2 may exert its anxiolytic effects in male MS rats by a compensatory increase in the acetylation of the OTR promoter to overcome reduced OT levels in the BNST.

Estradiol regulates responsiveness of the dorsal premammillary nucleus of the hypothalamus and affects fear- and anxiety-like behaviors in female rats.

Research suggests a causal link between estrogens and mood. Here, we began by examining the effects of estradiol (E2 ) on rat innate and conditioned defensive behaviors in response to cat odor. Second, we utilized whole-cell patch clamp electrophysiological techniques to assess noradrenergic effects on neurons within the dorsal premammillary nucleus of the hypothalamus (PMd), a nucleus implicated in fear reactivity, and their regulation by E2 . Our results show that E2 increased general arousal and modified innate defensive reactivity to cat odor. When ovariectomized females treated with E2 as opposed to oil were exposed to cat odor, they showed elevations in risk assessment and reductions in freezing, indicating a shift from passive to active coping. In addition, animals previously exposed to cat odor showed clear cue + context conditioning 24 h later. However, although E2 persisted in its effects on general arousal in the conditioning task, its effects on fear disappeared. In the patch clamp experiments noradrenergic compounds that typically induce fear clearly excited PMd neurons, producing depolarizations and action potentials. E2 treatment shifted some excitatory effects of noradrenergic agonists to inhibitory, possibly by differentially affecting α- and ß-adrenoreceptors. In summary, our results implicate E2 in general arousal and fear reactivity, and suggest these may be governed by changes in noradrenergic responsivity in the PMd. These effects of E2 may have ethological relevance, serving to promote mate seeking even in contexts of ambiguous threat and shed light on the involvement of estrogen in mood and its associated disorders.

Cortagine infused into the medial prefrontal cortex attenuates predator-induced defensive behaviors and Fos protein production in selective nuclei of the amygdala in male CD1 mice.

Corticotropin-releasing factor (CRF) plays an essential role in coordinating the autonomic, endocrine and behavioral responses to stressors. In this study, we investigated the role of CRF within the medial prefrontal cortex (mPFC) in modulating unconditioned defensive behaviors, by examining the effects of microinfusing cortagine a selective type-1 CRF receptor (CRF1) agonist, or acidic-astressin a preferential CRF1 antagonist, into the mPFC in male CD-1 mice exposed to a live predator (rat exposure test--RET). Cortagine microinfusions significantly reduced several indices of defense, including avoidance and freezing, suggesting a specific role for CRF1 within the infralimbic and prelimbic regions of the mPFC in modulating unconditioned behavioral responsivity to a predator. In contrast, microinfusions of acidic-astressin failed to alter defensive behaviors during predator exposure in the RET. Cortagine microinfusions also reduced Fos protein production in the medial, central and basomedial, but not basolateral subnuclei of the amygdala in mice exposed to the rat predatory threat stimulus. These results suggest that CRF1 activation within the mPFC attenuates predator-induced unconditioned anxiety-like defensive behaviors, likely via inhibition of specific amygdalar nuclei. Furthermore, the present findings suggest that the mPFC represents a unique neural region whereby activation of CRF1 produces behavioral effects that contrast with those elicited following systemic administration of CRF1 agonists.

A Microfluidic Approach to Pulsatile Delivery of Drugs for Neurobiological Studies.

We present an innovative microfluidic approach to transcranial delivery of small quantities of drugs in brief time pulses for neurobiological studies. The approach is based on a two-stage process of consecutive drug dispensing and delivery, demonstrated by a device featuring a fully planar design in which the microfluidic components are integrated in a single layer. This 2-D configuration offers ease in device fabrication and is compatible to diverse actuation schemes. A compliance-based and normally closed check valve is used to couple the microchannels that are responsible for drug dispensing and delivery. Brief pneumatic pressure pulses are used to mobilize buffer and drug solutions, which are injected via a cannula into brain tissue. Thus, the device can potentially allow transcranial drug delivery and can also be potentially extended to enable transdermal drug delivery. We have characterized the device by measuring the dispensed and delivered volumes under varying pneumatic driving pressures and pulse durations, the standby diffusive leakage, and the repeatability in the delivery of multiple pulses of drug solutions. Results demonstrate that the device is capable of accurately dispensing and delivering drug solutions 5 to 70 nL in volume within time pulses as brief as 50 ms, with negligible diffusive drug leakage over a practically relevant time scale. Furthermore, testing of pulsatile drug delivery into intact mouse brain tissue has been performed to demonstrate the potential application of the device to neurobiology.

Immunocytochemical characterization of pacinian-like corpuscles in the labia minora of prepubertal girls.

STUDY OBJECTIVE: To better understand the precise role of sensory corpuscles within the female external genitalia. DESIGN: After IRB approval, waste tissue samples were obtained from 10 normal girls (aged 2-9 years) who underwent surgery for labial fusion. Immunocytochemistry against protein gene product 9.5 (PGP 9.5), neuron-specific enolase (NSE), vasoactive intestinal peptide (VIP), 5-hydroxytryptamine transporter (5HTT), 5-hydroxytryptamine receptor 1A (5HT1A), Neuronal Peptide Y (NPY), neuronal nitric oxide synthase (nNOS), and estrogen receptors (ER) α and ß was performed. RESULTS: Pacinian-like corpuscles were identified in epithelium of labia minora of prepubertal girls. A central structure composed of an axon surrounded by a central core, outer core, external capsule, surrounded by encapsulated stroma, and a subsidiary innervation in the outer aspect of the corpuscle stroma stained for PGP 9.5 in the outer core and layers of the external capsule, NSE positive cells in layers of the outer core, 5HTT in stroma of the corpuscle and cells located in layers of the outer core, 5HT1A in cells of outer core, NPY in stroma of the corpuscle, and nNOS in external core and external capsule of the central structure. ERα was present in stroma, external core, and external capsule, and ERß in stroma of the corpuscle with subsidiary innervation in the stroma positive to PGP 9.5, VIP, and NPY. CONCLUSION: PGP 9.5, NSE, ERα, nNOS, and 5HTT immunoreaction detected in the outer core and external capsule could indicate these areas may play an important role in the functional aspects of the Pacinian-like corpuscle.

Persistent increase in hypothalamic arginine vasopressin gene expression during protracted withdrawal from chronic escalating-dose cocaine in rodents.

Arginine vasopressin (AVP) from the paraventricular nucleus (PVN) of hypothalamus has important roles in regulation of the hypothalamic-pituitary-adrenal (HPA) axis and stress-related behaviors during chronic stress. It is unknown, however, whether AVP in the PVN is involved in the modulation of HPA activity after chronic cocaine exposure. Here, we examined the gene expression alterations of AVP in the hypothalamus, and V1b receptor and pro-opiomelanocortin (POMC) in the anterior pituitary, as well as HPA hormonal changes, in Fischer rats after chronic cocaine and withdrawal, using two different chronic (14-day) 'binge' pattern administration regimens: steady-dose cocaine (SDC, 45 mg/kg/day) and escalating-dose cocaine (EDC, 45 up to 90 mg/kg/day). There was a significant (7-fold) plasma adrenocorticotropic hormone (ACTH) elevation after chronic EDC (but not SDC), coupled with increased V1b and POMC mRNA levels in the anterior pituitary. From acute (1-day) to protracted (14-day) withdrawal from chronic EDC (but not from SDC), we found persistent elevations of both plasma ACTH and corticosterone levels and AVP mRNA levels in the PVN. Selective V1b antagonist SSR149415 (5 mg/kg) attenuated acute withdrawal-induced HPA activation after EDC. To study potential roles of endogenous opioids in modulating the AVP gene, we administered naloxone (1 mg/kg); we found that opioid receptor antagonism increased AVP mRNA levels in cocaine-naive rats, but not in cocaine-withdrawn rats, suggesting less tonic opioid inhibition of PVN AVP neurons after chronic EDC. To assess the effects of cocaine withdrawal on sub-populations of PVN AVP neurons, we utilized AVP-enhanced green fluorescent protein (EGFP) promoter transgenic mice and found that acute withdrawal following chronic EDC increased the number of AVP-EGFP neurons in the parvocellular PVN (pPVN). These results suggest that during protracted withdrawal, enhanced pPVN AVP gene expression is associated with persistent elevations of basal HPA activity; a hyposensitivity of PVN AVP gene expression to naloxone is indicative of reduced opioidergic tone. Our studies indicate that the AVP and its V1b receptor system may be a potential therapeutic target for treating anxiety and depressive symptoms associated with cocaine addiction.

Effects of chronic social defeat on behavioral and neural correlates of sociality: Vasopressin, oxytocin and the vasopressinergic V1b receptor.

Chronic social stress in rodents produces behavioral and neuroendocrine patterns analogous to symptoms associated with psychopathologies in humans. Chronic social defeat in mice has been used to study the genetic and epigenetic precursors of stress-related social disorders. The neuropeptides arginine vasopressin (AVP) and oxytocin (OT) are released in central targets to modulate anti- and pro-social behaviors, respectively. AVP binds to V1a and V1b receptors (V1bRs) in discrete brain regions related to anxiety, depression and affiliative behaviors. Recent evidence suggests that V1bRs are involved in stress and anxiety and may be an attractive target for the treatment of associated disorders. In the present series of experiments, we aimed to evaluate the effects of chronic social defeat stress on: 1) anxiety-related behaviors in a social investigation paradigm and their potential modulation by an acute dose of SSR149415, a V1bR antagonist; 2) AVP and Fos protein levels in the paraventricular nucleus of the hypothalamus (PVN) and; 3) AVP- and OT-receptor (OTR) mRNA levels in brain regions associated with sociality. When compared to undefeated animals, socially defeated mice exhibited an anxiogenic behavioral profile towards a novel male conspecific, with SSR149415 partly attenuating these effects. Histochemistry using immunofluorescence showed defeat produced significant elevations of Fos and double labeling of AVP and Fos proteins in the paraventricular nucleus of the hypothalamus (PVN). SSR149415 attenuated the effects of defeat on Fos and AVP/Fos double labeling, consistent with an anxiolytic effect. Defeated mice showed elevated levels of OTR mRNA levels in the lateral septum (LS) in addition to increased V1bR and OTR mRNA in the medial amygdala (MeA). We suggest the involvement of V1bRs and OTRs in a circuit involving the PVN, MeA and LS in the effects of defeat on sociality. SSR149415 attenuated anxiogenesis in the social investigation model and both Fos and AVP/Fos labeling, suggesting V1bRs are an attractive target for the treatment of anxiety in general and disorders of sociality in particular.

Maternal separation modulates short-term behavioral and physiological indices of the stress response.

Early-life stress produces an anxiogenic profile in adulthood, presumably by activating the otherwise quiescent hypothalamic-pituitary-adrenal (HPA) axis during the vulnerable 'stress hyporesponsive period'. While the long-term effects of such early-life manipulations have been extensively characterized, little is known of the short-term effects. Here, we compared the short-term effects of two durations of maternal separation stress and one unseparated group (US) on behavioral and physiological indices of the stress response in rat pups. Separations included 3h on each of 12days, from postnatal day (PND) 2 to 13 (MS2-13) and 3days of daily, 6-h separation from PND11-13 (MS11-13). On PND14 (Experiment 1), both MS2-13 and MS11-13 produced marked reductions in freezing toward an adult male conspecific along with reduced levels of glucocorticoid type 2 (GR) and CRF type-1 (CRF(1)) receptor mRNA in the hippocampus. Group MS2-13 but not MS11-13 produced deficits in stressor-induced corticosterone secretion, accompanied by reductions in body weight. Our results suggest that GR and/or CRF(1) levels, not solely the magnitude of corticosterone secretion, may be involved in the modulation of freezing. In a second experiment, we aimed to extend these findings by testing male and female separated and unseparated pups' unconditioned defensive behaviors to cat odor on PND26, and subsequent cue+context conditioning and extinction throughout postnatal days 27-32. Our results show that maternal separation produced reductions in unconditioned freezing on PND26, with MS2-13 showing stronger deficits than MS11-13. However, separation did not affect any other defensive behaviors. Furthermore, separated rats failed to show conditioned freezing, although they did avoid the no-odor block conditioned cue. There were no sex differences other than weight. We suggest that maternal separation may have produced these changes by disrupting normal development of hippocampal regions involved in olfactory-mediated freezing, not in mechanisms of learning and memory per se. These findings may have direct relevance for understanding the mechanisms by which early-life adverse experiences produce short-term and lasting psychopathologies.

Effects of acidic-astressin and ovine-CRF microinfusions into the ventral hippocampus on defensive behaviors in rats.

This study investigated a possible role for ventral hippocampal corticotropin-releasing factor (CRF) in modulating both unconditioned and conditioned defensive behaviors by examining the effects of pre-training ventral hippocampal ovine-CRF (oCRF) or acidic-astressin ([Glu(11,16)]Ast) microinfusions in male Long-Evans hooded rats exposed to various threat stimuli including the elevated plus-maze (EPM) (oCRF), cat odor (oCRF and [Glu(11,16)]Ast) and a live cat ([Glu(11,16)]Ast). Unconditioned defensive behaviors were assessed during threat exposure, while conditioned defensive behaviors were assessed in each predator context 24 h after the initial threat encounter. Pre-training infusions of the CRF(1) and CRF(2) receptor agonist oCRF significantly increased defensive behaviors during both the unconditioned and conditioned components of the cat odor test, as well as exposure to the EPM. In contrast to the behavioral effects of oCRF microinfusions, the CRF(1) and CRF(2) receptor antagonist [Glu(11,16)]Ast significantly decreased defensive behaviors during exposure to cat odor, while producing no discernible effects following a second injection in the cat exposure test. During conditioned test trials, pre-training infusions of [Glu(11,16)]Ast also significantly reduced defensive behaviors during re-exposure to both predator contexts. These results suggest a specific role for ventral hippocampal CRF receptors in modulating anxiety-like behaviors in several ethologically relevant animal models of defense.

Cortagine: behavioral and autonomic function of the selective CRF receptor subtype 1 agonist.

Corticotropin-releasing factor (CRF) is a neuropeptide and mediating component of neuroendocrine, autonomic, and behavioral processes associated with the stress response. The two receptor subtypes identified in the mammalian brain, CRF receptor subtype 1 (CRF1) and CRF2, are suggested to differentially modulate these processes. Manipulation of these receptors with selective CRF compounds and transgenic models has revealed, in most studies, a clear potentiation of the stress response through central activation of CRF1. However, pharmacological activation of CRF restricted to CRF1 has been limited by the availability of selective peptidic compounds. Recently, a highly selective CRF1 agonist, cortagine, has been developed. It was synthesized from chimeric intermediate sequences of ovine CRF, sauvagine, and human/rat CRF into a highly soluble peptide with strong affinity for CRF1 (IC(50) < 5 nM) and a very low binding preference for CRF2 (IC(50) > 500 nM). Affinity for the CRF binding protein (IC(50) > 1,000 nM) can be abolished by the addition of a glutamate residue on position 21 of the cortagine peptide sequence. Cortagine has recently been tested in a variety of preclinical models of behavior including the elevated-plus-maze (EPM), forced swim test (FST), homecage, and rat exposure test (RET). Preliminary characterization in the EPM and FST suggested that this compound elicits anxiogenic and antidepressant-like effects, respectively. Additional testing in the homecage and RET, which targets various elements of behavior, directs to a more potent anxiogenic profile of cortagine. In this review, we discuss the behavioral findings and the tests used to measure these effects. Finally, we also discuss preliminary findings of autonomic activation obtained by central injection of cortagine that support CRF1 involvement in the modulation of heart rate and heart rate variability.

A pinch or a lesion: a reconceptualization of biting consequences in mice.

Intruder and resident male colony mice exhibit an array of distinct defensive and offensive behaviors. Intruders typically show more boxing, flight, defensive sideways position, on the back position and general locomotion, while residents exhibit higher levels of attack, olfactory investigation, aggressive grooming, and biting, with a preference for dorsal bite locations. Here, analysis of bite locations on the body of the intruder mice showed that the majority of bites produced few lesions (i.e. actual puncturing of the skin) when compared to scrapes or no markings. Most bites were directed to the back of the opponent animal with very few bites directed towards the opponents' vulnerable ventrum. In particular, bites directed at the relatively hairless ventrum produced no lesions. These findings, along with previous work on mice and rats, suggest that intraspecific offense with preferred target sites for biting, facilitates an effective but largely nonwounding interaction between resident and intruder mice. Furthermore, bruise and wound analyses suggest an association between bite targets and tissue damage. The preference for specific bite locations may be complimented by a differential intensity of attack, with the back attracting the strongest bites and the ventrum the weakest. This apparent nonwounding fighting pattern contradicts the current evaluation of rodent wounding severity in this paradigm and can therefore refine the usage of this model and of the protocols associated with it.

CRF type 1 receptors in the dorsal periaqueductal gray modulate anxiety-induced defensive behaviors.

The dorsal periaqueductal gray (dPAG) is involved in defensive coping reactions to threatening stimuli. Corticotropin releasing factor (CRF) is substantially implicated as a direct modulator of physiological, endocrine and behavioral responses to a stressor. Previous findings demonstrate a direct role of the central CRF system in dPAG-mediated defensive reactions toward a threatening stimulus. These include anxiogenic behaviors in the elevated plus maze (EPM) in rats and defensive reactions in both the mouse defense test battery (MDTB) and rat exposure test (RET) paradigms in mice. Furthermore, CRF was shown to directly and dose-dependently excite PAG neurons in vitro. The aim of the present series of experiments was to directly evaluate the role of the CRF1 receptor (CRF1) in dPAG-induced defensive behaviors in the MDTB and the RET paradigms. For this purpose, cortagine, a novel CRF1-selective agonist, was directly infused into the dPAG. In the RET the high dose of cortagine (100 ng) significantly affected spatial avoidance measures and robustly increased burying behavior, an established avoidance activity, while having no effects on behaviors in the MDTB. Collectively, these results implicate CRF1 in the dPAG as a mediator of temporally and spatially dependent avoidance in response to controllable and constant stimuli.

Effects of intra-PAG infusion of ovine CRF on defensive behaviors in Swiss-Webster mice.

The midbrain dorsal periaqueductal gray (DPAG) is part of the brain defensive system involved in active defense reactions to threatening stimuli. Corticotrophin releasing factor (CRF) is a peptidergic neurotransmitter that has been strongly implicated in the control of both behavioral and endocrine responses to threat and stress. We investigated the effect of the nonspecific CRF receptor agonist, ovine CRF (oCRF), injected into the DPAG of mice, in two predator-stress situations, the mouse defense test battery (MDTB), and the rat exposure test (RET). In the MDTB, oCRF weakly modified defensive behaviors in mice confronted by the predator (rat); e.g. it increased avoidance distance when the rat was approached and escape attempts (jump escapes) in forced contact. In the RET, drug infusion enhanced duration in the chamber while reduced tunnel and surface time, and reduced contact with the screen which divides the subject and the predator. oCRF also reduced both frequency and duration of risk assessment (stretch attend posture: SAP) in the tunnel and tended to increase freezing. These findings suggest that patterns of defensiveness in response to low intensity threat (RET) are more sensitive to intra-DPAG oCRF than those triggered by high intensity threats (MDTB). Our data indicate that CRF systems may be functionally involved in unconditioned defenses to a predator, consonant with a role for DPAG CRF systems in the regulation of emotionality.

Rat 22kHz ultrasonic vocalizations as alarm cries.

Rats incorporate circa 22kHz ultrasonic alarm cries into their defense pattern in response to a predator threat. These calls are dependent on conspecific presence, show gender differences, and tend to be emitted from a place of relative safety. Rats emit sonic defensive threat vocalizations when approached by a potential threat. These are emitted regardless of conspecific presence, and increase as a function of threat proximity, eventually culminating in defensive attack at close distances. Ample data from field studies suggest a similar division of vocalizations into alarm or warning cries, and defensive threat vocalizations, although both are often subsumed under the rubric of "alarm cries". A clear distinction between these types of calls is necessary for proper analysis of the evolutionary mechanisms responsible for the development and maintenance of each of them. Furthermore, the integration of data from field studies and laboratory experiments may prove useful in evaluation of the relationship between each type of cry and emotional (fear or anxiety-like) states in mammals.

Effects of lesions to the dorsal and ventral hippocampus on defensive behaviors in rats.

This study investigated the role of the hippocampus in both unconditioned and conditioned defensive behaviors by examining the effects of pretraining ibotenic acid lesions to the dorsal and ventral hippocampus in male Long-Evans hooded rats exposed to three types of threat stimuli: cat-odor, a live cat and footshock. Defensive behaviors were assessed during exposure to cat-odor and a live cat, and immediately following the presentation of footshock. Conditioned defensive behaviors were also assessed in each context 24 h after initial threat exposure. During both unconditioned and conditioned trials, dorsal hippocampal lesions failed to significantly alter any behavioral measure in each test of defense. In contrast, ventral hippocampal lesions significantly reduced unconditioned defensive behaviors during exposure to cat-odor without producing any observable effects during cat exposure. Furthermore, ventral lesions significantly attenuated conditioned defensive behaviors following the administration of footshock and during re-exposure to each context. These results suggest a specific role for the ventral, not dorsal, hippocampus in modulating anxiety-like behaviors in certain animal models of defense.