Role of inferior olive and thoracic IML neurons in nonshivering thermogenesis in rats

Removal of the midbrain tonic inhibitory mechanism on nonshivering thermogenesis (NST) results in increased temperatures of the interscapular brown adipose tissue (IBAT) and rectum (T(IBAT) and T(rec), respectively) via an enhanced central sympathetic output. Because it is unlikely that neurons (primary) of the midbrain inhibitory mechanism tonically inhibit the IBAT monosynaptically, there must be secondary or tertiary neurons posterior to the midbrain. Such neurons, therefore, may increase their activity during enhanced NST after removal of the midbrain tonic inhibition. The aim of the present experiments was to localize these secondary or tertiary neurons and establish descending neuronal pathway(s) that may project to the major NST effector IBAT. T(IBAT) and T(rec) increases induced by removal of the tonic inhibition by midbrain procaine microinjections were accompanied with appearance of c-Fos-positive neurons in the inferior olive (IO) and the intermediolateral (IML) cell column of the thoracic spinal cord. Electrical stimulation of and L-glutamate microinjections into the IO increased T(IBAT) and T(rec). Midbrain procaine-induced T(IBAT) and T(rec) increases were blocked by electrolytic IO lesions. These results suggest that central thermal signals produced from the lower midbrain are transmitted to IBAT through the IO and IML and that the IO has a role in the central sympathetic functions.     

Dorsomedial hypothalamic and brainstem pathways controlling thermogenesis in brown adipose tissue

1. The rostral medullary raphe pallidus contains sympathetic premotor neurons controlling thermogenesis in brown adipose tissue (BAT).

2. Disinhibition of neurons in the dorsomedial hypothalamus (DMH) stimulates BAT thermogenesis through activation of neurons in raphe pallidus.

3. An increase in BAT sympathetic outflow and BAT thermogenesis following microinjection of prostaglandin E2 into the preoptic area requires activation of both DMH neurons and raphe pallidus neurons.

4. DMH contains a population of neurons receiving a tonically- active GABAergic inhibition which mediate increases in BAT thermogenesis through stimulation of BAT sympathetic premotor neurons in raphe pallidus.     

Effect of beta-endorphin on the thermal excitability of preoptic neurons in the unanesthetized rabbit

The opioid peptide, beta-endorphin (beta-E), will promote changes in body temperature when injected into the brain. It is possible that beta-E alters body temperature by affecting the activity of thermoregulatory neurons in the preoptic anterior hypothalamus (POAH). Single unit activity in the POAH was recorded in unanesthetized rabbits while radiant heat was applied to the dorsal skin. Beta-E was then microinjected into the POAH, and the peripheral heating was repeated. Seventy-seven percent of the POAH neurons were responsive to skin heating. Beta-E and equal excitatory and inhibitory effects on warm-excited and warm-inhibited neurons. Four of six warm-excited neurons were converted to warm-inhibited or unresponsive following beta-E injection. Six out of ten warm-inhibited neurons were converted to warm-excited or unresponsive by beta-E. Beta-E-induced shifts in thermal excitability of POAH neurons may be responsible for the ability of POAH injections of beta-E to elevate body temperature in the rabbit.     

Brown adipose tissue thermogenesis contributes to fentanyl-evoked hyperthermia

Mu-opioid receptor activation increases body temperature and affects cardiovascular function. In the present study, fentanyl was administered intravenously [100 mug/kg (300 nmol/kg) iv] and intracerebroventricularly [3.4 mug (10 nmol) in 10 microl icv] in urethane-chloralose-anesthetized, artificially ventilated rats. Increases in brown adipose tissue (BAT) sympathetic nerve activity (SNA) (peak, +326% of control), BAT temperature (peak, +0.8 degrees C), renal SNA (peak, +146% of control), and heart rate (HR; peak, +32 beats/min) produced by intravenous fentanyl were abolished by premamillary transection of the neuraxis but were mimicked by intracerebroventricular administration of fentanyl, which also increased arterial pressure (AP; peak, +12 mmHg). Pretreatment with the opioid antagonist naloxone (100 nmol in 10 microl icv) eliminated the intracerebroventricular fentanyl-evoked responses. Microinjection of glycine (0.5 M, 60 nl) to inhibit local neurons in the rostral raphe pallidus (RPa) selectively reversed the intracerebroventricular fentanyl-evoked increases in BAT SNA and HR, while the fentanyl-evoked excitation in RSNA, the pressor responses, and the tachycardic responses were reversed by inhibition of neurons in the rostral ventrolateral medulla (RVLM). Prior inhibition of neurons in the dorsomedial hypothalamus eliminated the intracerebroventricular fentanyl-evoked increases in BAT SNA, BAT temperature, and HR, but not those in RSNA or AP. These results indicate that activation of central mu-opioid receptors with fentanyl can elicit BAT thermogenesis and cardiovascular stimulation through excitation of the sympathetic outflows to BAT, kidney, and heart. Activation of neurons in the rostral RPa and RVLM are essential for the increases in BAT thermogenesis and renal sympathoexcitation, respectively, induced by activation of central mu-opioid receptors. BAT thermogenesis could contribute to fentanyl-evoked hyperthermia, particularly in infants where BAT plays a significant role in thermoregulation.     

Orexin-A regulates body temperature in coordination with arousal status

Orexins, hypothalamic neuropeptides, are involved in modulation of food intake and arousal status. To further examine their physiological roles in brain function, the effect of centrally administered orexin-A on body temperature was investigated in rats. Assessed by a telemetry sensor system implanted into the abdominal cavity, infusion of orexin-A into the third cerebroventricle (i3vt) increased body temperature in a dose-responsive manner. Expression of uncoupling protein 1 (UCP1) mRNA in brown adipose tissue (BAT), as a marker for peripheral thermogenesis, failed to increase after the infusion. Expression of UCP3 mRNA in skeletal muscle was up-regulated, whereas UCP2 in white adipose tissue was unchanged after the infusion. The resulting information indicates that orexin neurons regulate body temperature in coordination with arousal status independently of peripheral thermogenesis, which is regulated by BAT UCP1.     

The Role of Thermogenesis in Antipsychotic Drug‐induced Weight Gain

The administration of antipsychotic drugs to human patients or experimental animals leads to significant weight gain, which is widely presumed to be driven by hyperphagia; however, the contribution from energy expenditure remains unclear. These studies aim to examine the contribution of shifts in energy expenditure, particularly those involving centrally mediated changes in thermogenesis, to the body weight gain associated with the administration of olanzapine to female Sprague Dawley rats. Olanzapine (6 mg/kg/day orally) caused a transient increase in food intake but a maintained increase in body weight. When pair‐fed rats were treated with olanzapine, body weight continued to rise compared to vehicle‐treated rats, consistent with a reduction in energy expenditure. Brown adipose tissue (BAT) temperature, measured using biotelemetry devices, decreased immediately after the onset of olanzapine treatment and remained depressed, as did physical activity. UCP1 expression in interscapular BAT was reduced following chronic olanzapine treatment. An acute injection of olanzapine was preceded by an injection of a retrograde tracer into the spinal cord to evaluate the nature of the olanzapine‐activated neural pathway. Levels of Fos protein in a number of spinally projecting neurons within discrete hypothalamic and brainstem sites were elevated in olanzapine‐treated rats. Some of these neurons in the perifornical region of the lateral hypothalamus (LHA) were also Orexin A positive. These data collectively show a significant impact of thermogenesis (and physical activity) on the weight gain associated with olanzapine treatment. The anatomical studies provide an insight into the central neuroanatomical substrate that may subserve the altered thermogenic responses brought about by olanzapine.     

Ccl22/MDC, is a prostaglandin dependent pyrogen, acting in the anterior hypothalamus to induce hyperthermia via activation of brown adipose tissue

CC Chemokine ligand 22 (Ccl22) is a selective, high affinity ligand at the CC chemokine receptor 4 (Ccr4). We have identified cDNAs encoding both ligand and receptor of the Ccl22–Ccr4 pair in cDNA libraries of the anterior hypothalamus/pre-optic area (AH/POA) by PCR. The AH/POA is the key brain region where endogenous pyrogens have been shown to act on warm sensitive neurons to affect thermogenesis in brown adipose tissue (BAT) and other thermogenically responsive tissues. We show that functional Ccr4 receptors are present in the AH/POA neurons as injection of Ccl22 into the POA but not to other hypothalamic nuclei induces an increase in core body temperature as measured by radiotelemetry. Indomethacin (5 mg/kg s.c) pre-treatment markedly reduced the hyperthermia evoked by POA injection of Ccl22 (10 ng/0.5 ul) and thus suggests that this hyperthermia is mediated through cyclooxygenase activation and thus likely through the formation and action of the pyrogen prostaglandin E2. The temperature elevation involves a decrease in the respiratory exchange ratio and increased activation of the brown adipose tissue as demonstrated by ¹⁸F-FDG–PET imaging. We describe a novel role to the ligand Ccl22 and its receptor Ccr4 in the anterior hypothalamus in temperature regulation that depends on the synthesis of the endogenous pyrogen, prostaglandin E2.     

Glucoprivation in the ventrolateral medulla decreases brown adipose tissue sympathetic nerve activity by decreasing the activity of neurons in raphe pallidus

In urethane/α-chloralose anesthetized rats, cold exposure increased brown adipose tissue sympathetic nerve activity (BAT SNA: +699 ± 104% control). Intravenous administration of 2-deoxy-D-glucose (2-DG; 200 mg·ml(-1)·kg(-1)) reversed the cold-evoked activation of BAT SNA (nadir: 139 ± 36% of control) and decreased BAT temperature (-1.1 ± 0.2°C), expired CO(2) (-0.4 ± 0.1%), and core temperature (-0.5 ± 0.0). Similarly, unilateral nanoinjection of the glucoprivic agent 5-thioglucose (5-TG; 12 μg/100 nl) in the ventrolateral medulla (VLM) completely reversed the cold-evoked increase in BAT SNA (nadir: 104 ± 7% of control), and decreased T(BAT) (-1.4 ± 0.3°C), expired CO(2) (-0.2 ± 0.0%), and heart rate (-35 ± 10 beats/min). The percentage of rostral raphé pallidus (RPa)-projecting neurons in the dorsal hypothalamic area/dorsomedial hypothalamus that expressed Fos in response to cold exposure (ambient temperature: 4-10°C) did not differ between saline (28 ± 6%) and 2-DG (30 ± 5%) pretreated rats, whereas the percentage of spinally projecting neurons in the RPa/raphé magnus that expressed Fos in response to cold exposure was lower in 2-DG- compared with saline-pretreated rats (22 ± 6% vs. 42 ± 5%, respectively). The increases in BAT SNA evoked by nanoinjection of bicuculline in the RPa or by transection of the neuraxis at the pontomedullary border were resistant to inhibition by glucoprivation. These results suggest that neurons within the VLM play a role in the glucoprivic inhibition of BAT SNA and metabolism, that this inhibition requires neural structures rostral to the pontomedullary border, and that this inhibition is mediated by a GABAergic input to the RPa.     

Adaptive character of metabolism in Eothenomys miletus in Hengduan Mountains region during cold acclimation

Environmental factors play an important role in the seasonal adaptation of body mass and thermogenesis in small, wild mammals. The purpose of the present study was to test the hypothesis that ambient temperature was a cue to trigger the seasonal adjustments in body mass, energy intake, uncoupling protein 1 (UCP1) in brown adipose tissue (BAT), and other biochemical characteristics of Eothenomys miletus during 49 days of cold exposure. Our data demonstrated that cold acclimation induced a remarkable decrease in body mass, a significant increase in energy intake and metabolic rate, and high expression of UCP1 in BAT of E. miletus. Biochemical characteristics of BAT and liver respiration were also increased following cold acclimation. These data suggest that E. miletus reduced the body mass and increased energy intake and expenditure under cold acclimation. Increased expression of UCP1 was potentially involved in the regulation of energy metabolism and thermogenic capacity following cold acclimation.     

SR59230A, a beta-3 adrenoceptor antagonist, inhibits ultradian brown adipose tissue thermogenesis and interrupts associated episodic brain and body heating

Brown adipose tissue (BAT) thermogenesis occurs episodically in an ultradian manner approximately every 80-100 min during the waking phase of the circadian cycle, together with highly correlated increases in brain and body temperatures, suggesting that BAT thermogenesis contributes to brain and body temperature increases. We investigated this in conscious Sprague-Dawley rats by determining whether inhibition of BAT thermogenesis via blockade of beta-3 adrenoceptors with SR59230A interrupts ultradian episodic increases in brain and body temperatures and whether SR59230A acts on BAT itself or via sympathetic neural control of BAT. Interscapular BAT (iBAT), brain, and body temperatures, tail artery blood flow, and heart rate were measured in unrestrained rats. SR59230A (1, 5, or 10 mg/kg ip), but not vehicle, decreased iBAT, body, and brain temperatures in a dose-dependent fashion (log-linear regression P < 0.01, R(2) = 0.3, 0.4, and 0.4, respectively, n = 10). Ultradian increases in BAT, brain, and body temperature were interrupted by administration of SR59230A (10 mg/kg ip) compared with vehicle, resuming after 162 ± 24 min (means ± SE, n = 10). SR59230A (10 mg/kg ip) caused a transient bradycardia without any increase in tail artery blood flow. In anesthetized rats, SR59230A reduced cooling-induced increases in iBAT temperature without affecting cooling-induced increases in iBAT sympathetic nerve discharge. Inhibition of BAT thermogenesis by SR59230A, thus, reflects direct blockade of beta-3 adrenoceptors in BAT. Interruption of episodic ultradian increases in body and brain temperature by SR59230A suggests that BAT thermogenesis makes a substantial contribution to these increases.     

Stress-induced hyperthermia is not mediated by brown adipose tissue in mice

Psychological stress leads to sympathetically mediated increases in body temperature. Brown adipose tissue (BAT) is often thought to be the main organ to produce heat in response to sympathetic activation. However, we have previously shown that the hyperthermia evoked by conditioned fear in rats is not the result of thermogenesis in the interscapular area of the back, where the largest deposit of BAT is found. Stress-induced hyperthermia is widely used as an anxiety indicator in mice. We thus sought to verify if this response can be attributed to BAT thermogenesis. Eight C57BL/6 mice were shaved in the interscapular and lumbar back areas prior to testing. Animals received injections of 20 mg/kg dl-propranolol or saline and were placed in either an open field or 4 °C enclosure for 30 min. Infrared thermographic images were taken each minute to record interscapular, lumbar and tail skin temperatures. Propranolol reduced the stress-induced hyperthermia observed during open field exposure (p<0.01), as indicated by the lumbar back skin temperature. Nevertheless, the difference between interscapular and lumbar skin temperatures remained constant, suggesting that this hyperthermia was not caused by BAT thermogenesis. There was no observable effect of propranolol on behavior, as animals remained active throughout the test. In contrast, the difference between interscapular and lumbar back skin temperature was increased by 2 °C during cold exposure. This increase was abolished after propranolol (p<0.001), indicating BAT thermogenesis during this challenge. Hence, just as rats exposed to conditioned fear, mice exposed to an open field display a stress-induced hyperthermia that is not caused by BAT thermogenesis.     

The dorsomedial hypothalamus: a new player in thermoregulation

Neurons in the dorsomedial hypothalamus (DMH) play key roles in physiological responses to exteroceptive ("emotional") stress in rats, including tachycardia. Tachycardia evoked from the DMH or seen in experimental stress in rats is blocked by microinjection of the GABA(A) receptor agonist muscimol into the rostral raphe pallidus (rRP), an important thermoregulatory site in the brain stem, where disinhibition elicits sympathetically mediated activation of brown adipose tissue (BAT) and cutaneous vasoconstriction in the tail. Disinhibition of neurons in the DMH also elevates core temperature in conscious rats and sympathetic activity to least significant difference interscapular BAT (IBAT) and IBAT temperature in anesthetized preparations. The latter effects are blocked by microinjection of muscimol into the rRP, while microinjection of muscimol into either the rRP or DMH suppresses increases in sympathetic nerve activity to IBAT, IBAT temperature, and core body temperature elicited either by microinjection of PGE(2) into the preoptic area (an experimental model for fever), or central administration of fentanyl. Neurons concentrated in the dorsal region of the DMH project directly to the rRP, a location corresponding to that of neurons trans-synaptically labeled from IBAT. Thus these neurons control nonshivering thermogenesis in rats, and their activation signals its recruitment in diverse experimental paradigms. Evidence also points to a role for neurons in the DMH in thermoregulatory cutaneous vasoconstriction, shivering, and endocrine adjustments. These directions provide intriguing avenues for future exploration that may expand our understanding of the DMH as an important hypothalamic site for the integration of autonomic, endocrine, and behavioral responses to diverse challenges.     

Changes of characteristics of preoptic neurons and NA metabolism in hypothalamus of ground squirrel (Citelleus Dautieus) in different seasons and hibernating phases

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Effect of phosphatidylcholine on the body temperature and activity of posterior hypothalamus neurons in animals

The experiments on rats and rabbits have shown that exogenous phosphatidyl choline (PC) was capable of altering the body temperature and bioelectrical activity of posterior hypothalamus neurons following intravenous and intracerebroventricular administration. Intracerebroventricular PC was more effective in raising the body temperature of rats. The experiments on rabbits have demonstrated that the influence of PC (intravenous administration) on the body temperature depended on the initial body temperature. In rabbits, the changes in the impulse activity of certain non-thermosensitive posterior hypothalamus neurons induced by intracerebroventricular PC administration were found to be dependent on the initial firing rates. PC inhibited the increase in bioelectrical activity of thermosensitive neurons in posterior hypothalamus caused by the rise in the brain temperature secondary to body temperature elevation.     

Changes of characteristics of preoptic neurons and NA metabolism in hypothalamus of ground squirrel (Citelleus Dautieus) in different seasons and hibernating phases

The unit firing activities of neurons in the preoptic area (POA) of ground squirrel hypothalamic tissue slices were recorded and the metabolism of NA in hypothalamus was measured with high performance liquid chromatography (HPLC). Thermosensitivity, proportions, the critical temperature (Tc) and the lowest temperature (TL) of firing activity of the above-mentioned neurons, and NA metabolism in hypothalamus were compared in different seasons and hibernating phases. In comparison with that in summer euthermar, it was shown that (i) the percentage and thermosensitivity of the POA neurons varied respectively in the hibernating phases; (ii) TL and Tc of the POA neurons in winter, both euthermar and hibernation, were markedly decreased; (iii) the POA neurons in hibernation became much more sensitive to NA, and the response of cold-sensitive neurons to NA changed from inhibiting pattern in summer to exciting one in hibernation; (iv) the contents and metabolism of NA in hypothalamus decreased significantly in the entering phase and deep hibernation phase, while the metabolism of NA increased remarkably in the arousal phase. These changes might explain the regulatory mechanism how ground squirrel actively decreases body temperature (Tb) in entering into hibernation and quickly recovers body temperature in arousal phase. Project supported by the National Natural Science Foundation of China (Grant Nos. 39230060 and 39570100)     

Effects of NMDA and non-NMDA ionotropic glutamate receptors in the medial preoptic area on body temperature in awake rats

Glutamate when microinjected at the medial preoptic area (mPOA) influences brain temperature (T_br) and body temperature (T_b) in rats. Glutamate and its various receptors are present at the mPOA. The aim of this study was to identify the contribution of each of the ionotropic glutamatergic receptors at the mPOA on changes in T_br and T_b in freely moving rats. Adult male Wistar rats (n=40) were implanted with bilateral guide cannula with indwelling styli above the mPOA. A telemetric transmitter was implanted at the peritoneum to record T_b and locomotor activity (LMA). A precalibrated thermocouple wire implanted near the hypothalamus was used to assess T_br. Specific agonist for each ionotropic glutamate receptor was microinjected into the mPOA and its effects on temperature and LMA were measured in the rats. The rats were also microinjected with the respective ionotropic receptor antagonists, 15 min prior to the microinjection of each agonist. Amongst amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), N-methyl-d-aspartate (NMDA) and kainic acid, AMPA increased T_b and LMA when injected at the mPOA. Specific antagonists for AMPA receptors was able to attenuate this increase (p<0.005). Pharmacological blockade of NMDA was able to lower T_br only. Microinjection of kainic acid and its antagonist had no effect on the variables. The finding of the study suggests that activation of the AMPA receptors at the mPOA, leads to the rise in body temperature.     

暖温经历对雌性黑线仓鼠能量代谢、产热和体脂含量的影响

能量代谢的生理调节是小型哺乳动物应对不同环境温度的重要策略之一,为探讨暖温下代谢产热在体重和体脂适应性调节中的作用和机理,本研究将雌性黑线仓鼠(Cricetulus barabensis)暴露于暖温(30°C)1个月、3个月和4个月,测定体重、摄入能、代谢产热、体脂含量、褐色脂肪组织(BAT)细胞色素c氧化酶(COX)活性和解偶联蛋1 (UCP1) mRNA表达等。结果显示,暖温对黑线仓鼠体重无显著影响,但使脂肪含量显著增加。与室温组相比(21°C),暖温组消化率显著升高,但摄入能和消化能显著降低;暖温下非颤抖性产热(NST)显著降低,脑、肝脏和心脏COX活性、BAT COX活性和UCP1 mRNA的表达显著下调。结果表明,暖温下降低代谢产热补偿了能量摄入的减少,机体处于正能量平衡状态,是脂肪含量显著增加的主要原因之一。脑、肝脏、心脏和BAT代谢活性降低是代谢产热降低的主要机制,与脂肪累积有关。     

Activation of 5-HT1A receptors in raphe pallidus inhibits leptin-evoked increases in brown adipose tissue thermogenesis

To elucidate the central neural pathways contributing to the thermogenic component of the autonomic response to intravenous administration of leptin, experiments were conducted in urethane-chloralose-anesthetized, ventilated rats to address 1) the role of neurons in the rostral ventromedial medulla, including raphe pallidus (RPa), in the leptin-evoked stimulation of brown adipose tissue (BAT) sympathetic nerve activity (SNA); and 2) the potential thermolytic effect of 5-hydroxytryptamine(1A) (5-HT(1A)) receptors on RPa neurons that influence BAT thermogenesis. Leptin (1 mg/kg) administration increased BAT SNA by 1,219% of control, BAT temperature by 2.8 degrees C, expired CO(2) by 1.8%, heart rate by 90 beats/min, and mean arterial pressure by 12 mmHg. Microinjection of the 5-HT(1A) receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) into RPa resulted in a prompt and sustained reversal of the leptin-evoked stimulation of BAT SNA, BAT thermogenesis, and heart rate, with these variables returning to their pre-leptin control levels. Subsequent microinjection of the selective 5-HT(1A) receptor antagonist WAY-100635 into RPa reversed the BAT thermolytic effects of 8-OH-DPAT, returning BAT SNA and BAT temperature to the elevated levels after leptin. In conclusion, activation of neurons in RPa, possibly BAT sympathetic premotor neurons, is essential for the increases in BAT SNA, BAT thermogenesis, and heart rate stimulated by intravenous administration of leptin. Neurons in RPa express 5-HT(1A) receptors whose activation leads to reversal of the BAT thermogenic and the cardiovascular responses to intravenous leptin, possibly through hyperpolarization of local sympathetic premotor neurons. These results contribute to our understanding of central neural substrates for the augmented energy expenditure stimulated by leptin.     

Anti-Apoptotic Protein Bcl-xL Expression in the Midbrain Raphe Region Is Sensitive to Stress and Glucocorticoids

Anti-apoptotic proteins are suggested to be important for the normal health of neurons and synapses as well as for resilience to stress. In order to determine whether stressful events may influence the expression of anti-apoptotic protein Bcl-xL in the midbrain and specifically in the midbrain serotonergic (5-HT) neurons involved in neurobehavioral responses to adverse stimuli, adult male rats were subjected to short-term or chronic forced swim stress. A short-term stress rapidly increased the midbrain bcl-xl mRNA levels and significantly elevated Bcl-xL immunoreactivity in the midbrain 5-HT cells. Stress-induced increase in glucocorticoid secretion was implicated in the observed effect. The levels of bcl-xl mRNA were decreased after stress when glucocorticoid elevation was inhibited by metyrapone (MET, 150 mg/kg), and this decrease was attenuated by glucocorticoid replacement with dexamethasone (DEX; 0.2 mg/kg). Both short-term stress and acute DEX administration, in parallel with Bcl-xL, caused a significant increase in tph2 mRNA levels and slightly enhanced tryptophan hydroxylase immunoreactivity in the midbrain. The increasing effect on the bcl-xl expression was specific to the short-term stress. Forced swim repeated daily for 2 weeks led to a decrease in bcl-xl mRNA in the midbrain without any effects on the Bcl-xL protein expression in the 5-HT neurons. In chronically stressed animals, an increase in tph2 gene expression was not associated with any changes in tryptophan hydroxylase protein levels. Our findings are the first to demonstrate that both short-term stress and acute glucocorticoid exposures induce Bcl-xL protein expression in the midbrain 5-HT neurons concomitantly with the activation of the 5-HT synthesis pathway in these neurons.