Mice with ablated adult brain neurogenesis are not impaired in antidepressant response to chronic fluoxetine

The neurogenesis hypothesis of major depression has two main facets. One states that the illness results from decreased neurogenesis while the other claims that the very functioning of antidepressants depends on increased neurogenesis. In order to verify the latter, we have used cyclin D2 knockout mice (cD2 KO mice), known to have virtually no adult brain neurogenesis, and we demonstrate that these mice successfully respond to chronic fluoxetine. After unpredictable chronic mild stress, mutant mice showed depression-like behavior in forced swim test, which was eliminated with chronic fluoxetine treatment, despite its lack of impact on adult hippocampal neurogenesis in cD2 KO mice. Our results suggest that new neurons are not indispensable for the action of antidepressants such as fluoxetine. Using forced swim test and tail suspension test, we also did not observe depression-like behavior in control cD2 KO mice, which argues against the link between decreased adult brain neurogenesis and major depression.     

Antidepressant drug-induced stimulation of mouse hippocampal neurogenesis is age-dependent and altered by early life stress

The continuous generation of new neurons in the adult hippocampus exhibits remarkable plasticity. Decreased neurogenesis is thought to underlie depression-like behaviors, and increased neurogenesis is thought to occur following antidepressant drug treatment. Studies on different strains of mice, however, yielded contrasting results with regard to the link between behavioral modifications induced by antidepressant drugs or environmental enrichment and changes in adult hippocampal neurogenesis. Therefore, we conducted a comparative study on the inbred strains Balb/c and C57Bl/6 that differ substantially in emotionality, stress reactivity, and behavioral responses to chronic antidepressant drugs. Quantitative assessments of progenitor cell proliferation and immature neuronal differentiation in the dentate gyrus revealed that, despite significantly different basal proliferation rates between both strains, neither strain exhibited changes in adult neurogenesis after exposure to early life stress or adult chronic fluoxetine treatment. A stimulatory effect of fluoxetine on adult hippocampal neurogenesis was only detected when treatment was initiated during adolescence, and this effect was abolished in mice exposed to early life stress, a prominent risk factor for developing adult-onset depression-like behaviors. Thus, in both strains of mice neither adult fluoxetine treatment nor adolescent fluoxetine treatment following early life stress exposure increased the proliferation and early differentiation of adult neural progenitor cells.     

Sex and repeated restraint stress interact to affect cat odor-induced defensive behavior in adult rats

The overall objective of the present experiment was to assess sex differences in the effects of repeated restraint stress on fear-induced defensive behavior and general emotional behavior. Groups of male and female Long-Evans rats received either daily restraint stress (stressed) or daily brief handling (nonstressed) for 21 consecutive days. On days 22-25, a number of behavioral tests were administered concluding with a test of defensive behavior in response to a predatory odor. Stressed and nonstressed males and females were exposed to a piece of cat collar previously worn by a female domestic cat (cat odor) or a piece of collar never worn by a cat (control odor) in a familiar open field containing a hide barrier. Rats displayed pronounced defensive behavior (increased hiding and risk assessment) and decreased nondefensive behavior (grooming, rearing) in response to the cat odor. Nonstressed females exposed to cat odor displayed less risk assessment behavior relative to nonstressed males exposed to cat odor. Restraint stress had little effect on defensive behavior in male rats but significantly increased risk assessment behaviors in females. Behavior on the Porsolt forced swim test (a measure of depression-like behavior) and the open field test (a measure of anxiety-like behavior) was not affected by stress or sex. These findings indicate the utility of the predator odor paradigm in detecting subtle shifts in naturally occurring anxiety-like behaviors that may occur differentially in males and females.     

Blockade of 2‐arachidonoylglycerol hydrolysis produces antidepressant‐like effects and enhances adult hippocampal neurogenesis and synaptic plasticity

The endocannabinoid ligand 2‐arachidonoylglycerol (2‐AG) is inactivated primarily by monoacylglycerol lipase (MAGL). We have shown recently that chronic treatments with MAGL inhibitor JZL184 produce antidepressant‐ and anxiolytic‐like effects in a chronic unpredictable stress (CUS) model of depression in mice. However, the underlying mechanisms remain poorly understood. Adult hippocampal neurogenesis has been implicated in animal models of anxiety and depression and behavioral effects of antidepressants. We tested whether CUS and chronic JZL184 treatments affected adult neurogenesis and synaptic plasticity in the dentate gyrus (DG) of mouse hippocampus. We report that CUS induced depressive‐like behaviors and decreased the number of bromodeoxyuridine‐labeled neural progenitor cells and doublecortin‐positive immature neurons in the DG, while chronic JZL184 treatments prevented these behavioral and cellular deficits. We also investigated the effects of CUS and chronic JZL184 on a form long‐term potentiation (LTP) in the DG known to be neurogenesis‐dependent. CUS impaired LTP induction, whereas chronic JZL184 treatments restored LTP in CUS‐exposed mice. These results suggest that enhanced adult neurogenesis and long‐term synaptic plasticity in the DG of the hippocampus might contribute to antidepressant‐ and anxiolytic‐like behavioral effects of JZL184. © 2014 Wiley Periodicals, Inc.     

Increase in neurogenesis and behavioural benefit after chronic fluoxetine treatment in Wistar rats

Objective –  Disturbances in hippocampal neurogenesis may be involved in the pathophysiology of depression and it has been argued that an increase in the generation of new nerve cells in the hippocampus is involved in the mechanism of action of antidepressants.
Materials and Methods –  Adult Wistar rats were treated with fluoxetine (10 mg/kg) 1 h, daily for 5 (subchronic) or 28 days (chronic) before the Novelty Suppressed Feeding test was performed. Cell proliferation and neurogenesis were analysed using the markers 5-bromo-deoxy-2'-uridine, Ki-67, and doublecortin.
Results –  A significant behavioural effect was found after 28 days of fluoxetine administration. However, no behavioural improvement was demonstrated after acute and subchronic treatment with fluoxetine. We further demonstrate that chronic antidepressant treatment increases cell proliferation as well as neurogenesis in the dentate gyrus, here using Wistar rats.
Conclusions –  In further development of antidepressants, neurogenesis may serve as an important parameter to examine the efficacy and mechanism of action of novel drugs.     

PI3K/AKT pathway mediates the antidepressant- and anxiolytic-like roles of hydrogen sulfide in streptozotocin-induced diabetic rats via promoting hippocampal neurogenesis

We have previously demonstrated that hydrogen sulfide (H₂S), the third endogenous gasotransmitter, ameliorates the depression- and anxiety-like behaviors in diabetic rats, but the underlying mechanism remains unclear. The present was aimed to investigate whether the hippocampal phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) pathway mediates H₂S-ameliorated depression- and anxiety-like behaviors in diabetic rats by improving the hippocampal neurogenesis. The depression-like behaviors were examined by Tail suspension test (TST), the anxiety-like behaviors were examined by Elevated plus maze test (EPM), and the locomotor activity was detected by Open Field Test (OFT). The expressions of doublecortin (DCX), neuron-specific nuclear protein (NeuN), glial fibrillary acidic protein (GFAP), p-AKT, and AKT in the hippocampus were determined by Western blot analysis. Results showed that NaHS, a donor of exogenous H₂S, not only activated the hippocampal PI3K/AKT pathway, as evidenced by the increase of phosphorylated AKT, but also favorably reversed streptozotocin (STZ)-disturbed hippocampal neurogenesis, as evidenced by the increases in the expressions of DCX and NeuN as well as the decrease in the expression of GFAP in the hippocampus of STZ-induced diabetic rats. Furthermore, inhibited PI3K/AKT pathway by LY294002 significantly abolished H₂S-exerted the improvement of hippocampal neurogenesis and the antidepressant- and anxiolytic-like effects in the STZ-induced diabetic rats. Taken together, these results uncover that the activation of hippocampal PI3K/AKT pathway plays an important role to restore hippocampal neurogenesis and subsequently to mediate the antidepressant- and anxiolytic-like roles of H₂S in STZ-induced diabetic rats and enhance our understanding of the robustness of H₂S as a therapeutic strategy for treatment of depression in diabetes mellitus.     

Neurogenesis-independent antidepressant-like effects on behavior and stress axis response of a dual orexin receptor antagonist in a rodent model of depression

Growing evidence indicates that an increase of orexin (or hypocretin) signaling is involved in the pathophysiology of major depression, but little is known regarding the causal link between the orexinergic system and depressive-like states. Here we blocked orexin receptors in mice subjected to unpredictable chronic mild stress (UCMS) to investigate putative antidepressant-like effects of this treatment, as well as the underlying mechanisms. BALB/c mice were exposed to 9 weeks of UCMS and from the third week onward treated daily with fluoxetine (20?mg/kg per day, per os) or with the dual orexin receptor antagonist almorexant (100?mg/kg per day, per os). The effects of UCMS regimen and pharmacological treatments were assessed by physical measures and behavioral testing. The dexamethasone suppression test was performed to examine the integrity of the negative feedback of the hypothalamic-pituitary-adrenal (HPA) axis, and immunohistochemical markers were used to assess cell proliferation (Ki-67), immature newborn neurons (doublecortin), and mature newborn neurons (5-bromo-2'-deoxyuridine/NeuN) in the dorsal and ventral parts of the hippocampus. Our results show that 7 weeks of fluoxetine or almorexant treatments counteract the UCMS-induced physical and behavioral alterations. Both treatments prevented the HPA axis dysregulation caused by UCMS, but only fluoxetine reversed the UCMS-induced decrease of hippocampal cell proliferation and neurogenesis, while chronic almorexant treatment decreased cell proliferation and neurogenesis specifically in the ventral hippocampus. Taken together, this is the first evidence that pharmacological blockade of the orexinergic system induces a robust antidepressant-like effect and the restoration of stress-related HPA axis defect independently from a neurogenic action.     

Brain interleukin-1 mediates chronic stress-induced depression in mice via adrenocortical activation and hippocampal neurogenesis suppression

Several lines of evidence implicate the pro-inflammatory cytokine interleukin-1 (IL-1) in the etiology and pathophysiology of major depression. To explore the role of IL-1 in chronic stress-induced depression and some of its underlying biological mechanisms, we used the chronic mild stress (CMS) model of depression. Mice subjected to CMS for 5 weeks exhibited depressive-like symptoms, including decreased sucrose preference, reduced social exploration and adrenocortical activation, concomitantly with increased IL-1 beta levels in the hippocampus. In contrast, mice with deletion of the IL-1 receptor type I (IL-1rKO) or mice with transgenic, brain-restricted overexpression of IL-1 receptor antagonist did not display CMS-induced behavioral or neuroendocrine changes. Similarly, whereas in wild-type (WT) mice CMS significantly reduced hippocampal neurogenesis, measured by incorporation of bromodeoxyuridine (BrdU) and by doublecortin immunohistochemistry, no such decrease was observed IL-1rKO mice. The blunting of the adrenocortical activation in IL-1rKO mice may play a causal role in their resistance to depression, because removal of endogenous glucocorticoids by adrenalectomy also abolished the depressive-like effects of CMS, whereas chronic administration of corticosterone for 4 weeks produced depressive symptoms and reduced neurogenesis in both WT and IL-1rKO mice. The effects of CMS on both behavioral depression and neurogenesis could be mimicked by exogenous subcutaneous administration of IL-1 beta via osmotic minipumps for 4 weeks. These findings indicate that elevation in brain IL-1 levels, which characterizes many medical conditions, is both necessary and sufficient for producing the high incidence of depression found in these conditions. Thus, procedures aimed at reducing brain IL-1 levels may have potent antidepressive actions.     

5-羟色胺1A受体激动剂8-OH-DPAT对癫痫合并抑郁神经发生的研究

目的探讨5-羟色胺1A(5-HT1A)受体与匹罗卡品诱导的癫痫大鼠合并抑郁海马齿状回神经发生的关系。方法从匹罗卡品诱导的慢性自发性颞叶癫痫大鼠中筛选出合并抑郁的大鼠3 2只,随机分成模型组、卡马西平(CBZ)组、CBZ+8-OH-DPAT低剂量(0.1 mg/kg)组、CBZ+8-OH-DPAT高剂量(1.0 mg/kg)组,每组8只。对照组8只,注射生理盐水(1 0 m l/kg)。药物干预后,制备大鼠脑片,利用免疫组织化学方法检测大鼠的神经发生。结果模型组海马齿状回神经发生较对照组明显增多,差异有统计学意义(P<0.0 5)。CBZ组、CBZ+8-OH-DPAT低剂量组、CBZ+8-OH-DPAT高剂量组较模型组神经发生明显增多,差异有统计学意义(P<0.0 5)。CBZ+8-OH-DPAT高剂量组较CBZ组、CBZ+8-OH-DPAT低剂量组神经发生明显增多,差异有统计学意义(P<0.0 5)。但CBZ组与CBZ+8-OH-DPAT低剂量组比较神经发生的差异没有统计学意义(P>0.0 5)。结论高剂量的5-HT1A受体激动剂8-OH-DPAT在实验的过程中能够增加癫痫合并抑郁大鼠的神经发生。     

Notch1信号系统与抑郁模型大鼠海马神经重塑障碍

目的 探讨Notch1信号系统在抑郁海马神经再生障碍中的作用.方法 选择行为学评分相近的68只Sprague-Dawley大鼠,分为对照组、对照+氟西汀组、慢性不可预知温和应激(CUMS)组,CUMS+氟西汀组,每组17只.应用CUMS建立抑郁模型后进行行为学评估;采用免疫组织化学方法检测大鼠海马神经干细胞的增殖和存活;采用实时定量聚合酶链反应和蛋白免疫印迹方法测定Notchl信号通路各个因子(NICD、Hes1、Hes5、Jag1)的基因及蛋白表达水平的改变.结果 (1)干预前,各组体质量、糖水偏好、旷场试验、强迫游泳评分的差异均无统计学意义(P>0.05);干预后,与对照组比较,CUMS组糖水偏好、水平得分和垂直得分降低,漂浮不动时间增加,差异均有统计学意义(P<0.001);与CUMS组比较,CUMS+氟西汀组糖水偏好、水平得分和垂直得分增加,漂浮不动时间降低,差异均有统计学意义(P<0.01);(2)神经干细胞的增殖和存活:与CUMS组(1900.33±104.10)比较,CUMS+氟西汀组(3047.61±158.29)神经干细胞的增殖数显著上升,差异有统计学意义(P<0.01);与CUMS组(1845.33±126.88)比较,CUMS+氟西汀组(2704.21±154.31)神经干细胞的存活数显著上升,差异有统计学意义(P<0.01);(3)海马Notch1信号通路基因和蛋白的表达:CUMS+氟西汀组小鼠抗大鼠Notch1(NICD)mRNA、Hes1 mRNA、Hes5 mRNA、Jag1 mRNA基因表达与CUMS组比较显著上升,差异均有统计学意义(P<0.01);CUMS+氟西汀组NICD、Hes5、Jag1蛋白水平与CUMS组比较显著上升,差异均有统计学意义(P<0.01).结论 Notch1信号系统可能参与慢性应激模型大鼠海马神经再生障碍;氟西汀可能通过上调Notch1信号系统改善海马神经再生,从而缓解大鼠抑郁症状.

Abstract：

Objective To investigate whether the effect of fluoxetine on hippocampal neurogenesis involves Notch1 signaling after chronic stress. Methods Sixty-eight male Sprague-Dawley rats were divided into control group, control + fluoxetine group, depression model group and depression model + fluoxetine group. Chronic unpredictable mild stress (CUMS) was used to make up depression animal model. The function of Notch1 signaling was measured by real-time PCR and western blotting. Simultaneously,hippocampal neurogenesis was monitored by assessing cell proliferation and survival. Results (1) Before starting CUMS protocol, the animals exhibited equivalent weight, sucrose preference, number of squares crossed, number of rearing, and immobility time in behavioral test. Twenty-eight days after CUMS protocol,these parameters were significantly difference in rats exposed to CUMS compared with the controls (sucrose preference, number of squares crossed, number of grooming and rearing, and immobility time, P<0. 01).Administration of fluoxetine was shown to dramatically improve the depression behavior (P<0. 01) .(2) The cell proliferation [(3047. 61 ± 158. 29) vs. (1900. 33 ± 104. 10)] and survive [(2704. 21 ±154. 31) vs. (1845.33 ± 126.88)] were increased after fluoxetine administration in rats with depression (P<0. 01). (3) Fluoxetine increased mRNA expressions of Notch1 signaling components [NICD mRNA (0. 23 ±0. 01) vs. (0. 10 ±0.01), Hes1 mRNA (0. 56 ±0.04) vs. (0. 28 ±0.02), Hes5 mRNA (0. 24 ±0.02) vs. (0.10 ±0.02), Jag1 mRNA (0.82 ±0.06) vs. (0.56 ±0.03)] in the rat hippocampus compared with the CUMS group (P<0. 01 or P<0. 001). Fluoxetine enhanced protein levels of Notch1 signaling components [NICD(1.99 ±0.07) vs. (0.53 ±0.10), Hes5(0. 64 ±0. 04) vs. (0.37 ±0.09),Jag1 (2. 34 ± 0. 13) vs. (0. 68 ± 0. 17)] in the rat hippocampus compared with the CUMS group (P <0.01). Conclusion The up-regulation of the Notch1 pathway with chronic fluoxetine administration might partly contribute to increased neurogenesis in the rat hippocampus with depression.     

Effects of social defeat stress and fluoxetine treatment on neurogenesis and behavior in mice that lack zinc transporter 3 (ZnT3) and vesicular zinc

Depression is a leading cause of disability worldwide, in part because the available treatments are inadequate and do not work for many people. The neurobiology of depression, and the mechanism of action of common antidepressant drugs such as selective serotonin reuptake inhibitors (SSRIs), is not well understood. One mechanism thought to underlie the effects of these drugs is upregulation of adult hippocampal neurogenesis. Evidence indicates that vesicular zinc is required for modulation of adult hippocampal neurogenesis, at least under some circumstances. Vesicular zinc refers to zinc that is stored in the synaptic vesicles of certain neurons, including in the hippocampus, and released in response to neuronal activity. It can be eliminated from the brain by deletion of zinc transporter 3 (ZnT3), as is the case in ZnT3 knockout mice. Here, we examined the effects of repeated social defeat stress and subsequent chronic treatment with the SSRI fluoxetine on behavior and neurogenesis in ZnT3 knockout mice. We hypothesized that fluoxetine treatment would increase neurogenesis and reverse stress‐induced behavioral symptoms in wild type, but not ZnT3 knockout, mice. As anticipated, stress induced persistent depression‐like effects, including social avoidance and anxiety‐like behavior. Fluoxetine decreased social avoidance, though the effect was not specific to the stressed mice, but did not affect anxiety‐like behavior. Surprisingly, stress increased the survival of neurons born 1 day after the last episode of defeat stress. Fluoxetine treatment also increased cell survival, particularly in wild type mice, though it did not affect proliferation. Our results did not support our hypothesis that vesicular zinc is required for the behavioral benefits of fluoxetine treatment. As to whether vesicular zinc is required for the neurogenic effects of fluoxetine, our results were inconclusive, warranting further investigation into the role of vesicular zinc in adult hippocampal neurogenesis.     

Alterations in circadian entrainment precede the onset of depression-like behavior that does not respond to fluoxetine

Growing evidence links adverse prenatal conditions to mood disorders. We investigated the long-term behavioral alterations induced by prenatal exposure to excess glucocorticoids (dexamethasone—DEX). At 12 months, but not earlier, DEX-exposed mice displayed depression-like behavior and impaired hippocampal neurogenesis, not reversible by the antidepressant fluoxetine (FLX). Concomitantly, we observed arrhythmic glucocorticoid secretion and absent circadian oscillations in hippocampal clock gene expression. Analysis of spontaneous activity showed progressive alterations in circadian entrainment preceding depression. Circadian oscillations in clock gene expression (measured by means of quantitative PCR) were also attenuated in skin fibroblasts before the appearance of depression. Interestingly, circadian entrainment is not altered in a model of depression (induced by methylmercury prenatal exposure) that responds to FLX. Altogether, our results suggest that alterations in circadian entrainment of spontaneous activity, and possibly clock gene expression in fibroblasts, may predict the onset of depression and the response to FLX in patients.     

Effects of antidepressant treatment on mice lacking brain‐derived neurotrophic factor expression through promoter IV

Brain‐derived neurotrophic factor (BDNF) is implicated in the pathophysiology of major depression; mice lacking BDNF expression through promoter IV (BDNF‐KIV) exhibit a depression‐like phenotype. We tested our hypothesis that deficits caused by promoter IV deficiency (depression‐like behavior, decreased levels of BDNF, and neurogenesis in the hippocampus) could be rescued by a 3‐week treatment with different types of antidepressants: fluoxetine, phenelzine, duloxetine, or imipramine. Each antidepressant reduced immobility time in the tail suspension test without affecting locomotor activity in the open field test in both BDNF‐KIV and control wild type mice, except that phenelzine increased locomotor activity in wild type mice and anxiety‐like behavior in BDNF‐KIV mice. The antidepressant treatments were insufficient to reverse decreased BDNF levels caused by promoter IV deficiency. No antidepressant treatment increased the hippocampal progenitors of either genotype, whereas phenelzine decreased the surviving progenitors in both genotypes. The antidepressant treatments differently affected the dendritic extension of hippocampal immature neurons: fluoxetine and imipramine increased extension in both genotypes, duloxetine increased it only in BDNF‐KIV mice, and phenelzine decreased it only in wild type mice. Interestingly, a saline‐only injection increased neurogenesis and dendrite extensions in both genotypes. Our results indicate that the behavioral effects in the tail suspension test by antidepressants do not require promoter IV‐driven BDNF expression and occur without a detectable increase in hippocampal BDNF levels and neurogenesis but may involve increased dendritic reorganisation of immature neurons. In conclusion, the antidepressant treatment demonstrated limited efficacy; it partially reversed the defective phenotypes caused by promoter IV deficiency but not hippocampal BDNF levels.     

Melatonin Augments the Effects of Fluoxetine on Depression-Like Behavior and Hippocampal BDNF–TrkB Signaling

Depression is a debilitating psychiatric disorder with a huge socioeconomic burden, and its treatment relies on antidepressants including selective serotonin reuptake inhibitors(SSRIs). Recently, the melatonergic system that is closely associated with the serotonergic system has been implicated in the pathophysiology and treatment of depression. However, it remains unknown whether combined treatment with SSRI and melatonin has synergistic antidepressant effects. In this study, we applied a sub-chronic restraint stress paradigm, and evaluated the potential antidepressant effects of combined fluoxetine and melatonin in adult male mice. Sub-chronic restraint stress(6 h/day for 10 days) induced depression-like behavior as shown by deteriorated fur state, increased latency to groom in the splash test, and increased immobility time in the forced-swim test. Repeated administration of either fluoxetine or melatonin at 10 mg/kg during stress exposure failed to prevent depression-like phenotypes. However,combined treatment with fluoxetine and melatonin at theselected dose attenuated stress-induced behavioral abnormalities. Moreover, we found that the antidepressant effects of combined treatment were associated with the normalization of brain-derived neurotrophic factor(BDNF)–tropomyosin receptor kinase B(Trk B) signaling in the hippocampus, but not in the prefrontal cortex. Our findings suggest that combined fluoxetine and melatonin treatment exerts synergistic antidepressant effects possibly by restoring hippocampal BDNF–Trk B signaling.     

Antidepressants recruit new neurons to improve stress response regulation

Recent research suggests an involvement of hippocampal neurogenesis in behavioral effects of antidepressants. However, the precise mechanisms through which newborn granule neurons might influence the antidepressant response remain elusive. Here, we demonstrate that unpredictable chronic mild stress in mice not only reduces hippocampal neurogenesis, but also dampens the relationship between hippocampus and the main stress hormone system, the hypothalamo-pituitary-adrenal (HPA) axis. Moreover, this relationship is restored by treatment with the antidepressant fluoxetine, in a neurogenesis-dependent manner. Specifically, chronic stress severely impairs HPA axis activity, the ability of hippocampus to modulate downstream brain areas involved in the stress response, the sensitivity of the hippocampal granule cell network to novelty/glucocorticoid effects and the hippocampus-dependent negative feedback of the HPA axis. Remarkably, we revealed that, although ablation of hippocampal neurogenesis alone does not impair HPA axis activity, the ability of fluoxetine to restore hippocampal regulation of the HPA axis under chronic stress conditions, occurs only in the presence of an intact neurogenic niche. These findings provide a mechanistic framework for understanding how adult-generated new neurons influence the response to antidepressants. We suggest that newly generated neurons may facilitate stress integration and that, during chronic stress or depression, enhancing neurogenesis enables a dysfunctional hippocampus to restore the central control on stress response systems, then allowing recovery.     

Lesions of structures showing FOS expression to cat presentation: effects on responsivity to a Cat, Cat odor, and nonpredator threat

Exposure of rats to a cat elicits Fos activity in a number of brain areas or structures. Based on hodological relationships of these, Canteras has proposed a medial hypothalamic defense system, with input from several forebrain sites. Both electrolytic and neurotoxic lesions of the dorsal premammillary nucleus, which shows the strongest Fos response to cat exposure, produce striking decrements in a number of defensive behaviors to a cat or to cat odor stimuli, but do not have a major effect on either postshock freezing, or responsivity to the odor of a female in estrus. Neurotoxic lesions of the medial amygdala produce decrements in defensiveness to predator stimuli, particularly odor stimuli, that are consistent with a view of this structure as involved with allomonal cues. While dorsal hippocampal lesions had little effect on responsivity to predator stimuli, neurotoxic lesions of the ventral hippocampus reduced freezing and enhanced a variety of nondefensive behaviors to both cat odor and footshock, with similar reductions in defensiveness during context conditioning tests for cat odor, cat exposure and footshock.

These results support the view that the dorsal premammillary nucleus is strongly and selectively involved in control of responsivity to predator stimuli. Structures with important input into the medial hypothalamic defense system appear also to be functionally involved with antipredator defensive behaviors, and these lesion studies may suggest specific hypotheses as to the particular defense functions of different areas.