"Imagine a clinical world without family systems thinking": Comment.

Comments on an editorial by C. T. Fogarty and L. B. Mauksch (see record 2017-56601-001). The editorial discussed collaborative family health care and the importance of family and social context to yield a comprehensive understanding of health. Jacobs agrees that family systemic thinking is an extremely helpful tool for clinicians, even if there's limited data to prove that. But he also thinks that systemic thinking in and of itself doesn't flatten the health care hierarchy and empower family members. (PsycINFO Database Record

Acceptance speech for the 2016 Don Bloch Award from the Collaborative Family Healthcare Association.

Presents the acceptance speech from Dr. Barry Jacobs for the 2016 Don Bloch Award from the Collaborative Family Healthcare Association (CFHA). (PsycINFO Database Record

The 2012 Don Bloch Award: presented by the Collaborative Family Healthcare Association to Larry Mauksch, MEd, October 5, 2012.

The Don Bloch Award is presented annually by the Collaborative Family Healthcare Association (CFHA) to a person who has made singular contributions to forwarding the cause of collaborative family health care. At the 2012 conference in Austin, Texas, the award was presented to Larry Mauksch of the Department of Family Medicine at the University of Washington. Three nominating talks given at that occasion and Larry's acceptance remarks are provided.

Activity-based anorexia is associated with reduced hippocampal cell proliferation in adolescent female rats.

Activity-based anorexia (ABA) is an animal model of anorexia nervosa that mimics core features of the clinical psychiatric disorder, including severe food restriction, weight loss, and hyperactivity. The ABA model is currently being used to study starvation-induced changes in the brain. Here, we examined hippocampal cell proliferation in animals with ABA (or the appropriate control conditions). Adolescent female Sprague-Dawley rats were assigned to 4 groups: control (24h/day food access), food-restricted (1h/day food access), exercise (24h/day food and wheel access), and ABA (1h/day food access, 24h/day wheel access). After 3 days of ABA, 5-bromo-2'-deoxyuridine (BrdU; 200mg/kg, i.p.) was injected and the rats were perfused 2h later. Brains were removed and subsequently processed for BrdU and Ki67 immunohistochemistry. The acute induction of ABA reduced cell proliferation in the dentate gyrus. This effect was significant in the hilus region of the dentate gyrus, but not in the subgranular zone, where adult neurogenesis occurs. Marked decreases in cell proliferation were also observed in the surrounding dorsal hippocampus and in the corpus callosum. These results indicate a primary effect on gliogenesis rather than neurogenesis following 3 days of ABA. For each brain region studied (except SGZ), there was a strong positive correlation between the level of cell proliferation and body weight/food intake. Future studies should examine whether these changes are maintained following long-term weight restoration and whether alterations in neurogenesis occur following longer exposures to ABA.

Tobacco smoke diminishes neurogenesis and promotes gliogenesis in the dentate gyrus of adolescent rats.

Brain disorders and environmental factors can affect neurogenesis and gliogenesis in the hippocampus. These studies investigated the effects of chronic exposure to tobacco smoke on progenitor cell proliferation and the survival and phenotype of new cells in the dentate gyrus of adolescent rats. The rats were exposed to tobacco smoke for 4h/day for 14 days. To investigate cell proliferation, the exogenous marker 5-bromo-2'-deoxyuridine (BrdU, 200mg/kg, ip) was administered 2h into the 4-h smoke exposure session on day 14. The rats were sacrificed 2-4h after the administration of BrdU. To investigate cell survival, the same dose of BrdU was administered 24h before the start of the 14-day smoke exposure period. These rats were sacrificed 24h after the last smoke exposure session. Tobacco smoke exposure decreased both the number of dividing progenitor cells (-19%) and the number of surviving new cells (-20%), labeled with BrdU in the dentate gyrus. The decrease in cell proliferation was not associated with an increase in apoptotic cell death, as shown by TUNEL analysis. Colocalization studies indicated that exposure to tobacco smoke decreased the number of new immature neurons (BrdU/DCX-positive) and transition neurons (BrdU/DCX/NeuN-positive) and increased the number of new glial cells (BrdU/GFAP-positive). These findings demonstrate that exposure to tobacco smoke diminishes neurogenesis and promotes gliogenesis in the dentate gyrus of adolescent rats. These effects may play a role in the increased risk for depression and cognitive impairment in adolescent smokers.

Suppression of hippocampal cell proliferation by short-term stimulant drug administration in adult rats.

Sleep loss is known to potently suppress adult hippocampal cell proliferation and neurogenesis. Whether sleep suppression following acute administration of stimulant drugs also decreases hippocampal cell proliferation is not known. The present study examined the effect of three mechanistically distinct stimulants (caffeine, methamphetamine and modafinil) on cell proliferation. To maximize sleep suppression, these drugs were administered to rats (three i.p. injections, once every 4 h) during their sleep period (i.e. 12-h light phase). At the end of the light phase, 5-bromo-2'-deoxyuridine (200 mg/kg, i.p.) was injected and animals were killed 2 h later. Polygraphic recordings and locomotor activity measurements confirmed the wake-promoting and sleep-suppressing actions of each treatment. Results indicate that caffeine (20 mg/kg), methamphetamine (1.5 mg/kg) and modafinil (300 mg/kg) differentially suppressed sleep (45-91%) and selectively reduced cell proliferation in the hilus (12-44%), these results being significant for both caffeine and modafinil. When the same experiment was repeated in the dark (active) phase, the suppressant effect on hippocampal cell proliferation was either absent or greatly attenuated. In a further experiment, the effect of acute modafinil treatment in the light phase was shown to persist for 3 weeks after BrdU administration. We hypothesize that the differential effect of the stimulant drugs in the light vs. dark phase is attributable primarily to sleep suppression in the light. As abuse of stimulant drugs invariably leads to disrupted sleep in humans, our results suggest that they may, at least in part, decrease hippocampal neurogenesis via sleep loss and thereby adversely affect hippocampal-dependent processes.

Effects of the hypnotic drug zolpidem on cell proliferation and survival in the dentate gyrus of young and old rats.

Sleep loss/disruption has been shown to suppress adult hippocampal neurogenesis. Whether the administration of hypnotic drugs, by promoting sleep, especially in older subjects, who typically exhibit poor sleep, has a beneficial effect on neurogenesis parameters is unknown. We examined the effects of zolpidem, a widely prescribed nonbenzodiazepine hypnotic, on cell proliferation and survival in the dentate gyrus of young ( approximately 2 1/2 months) and old ( approximately 13 months) male Sprague-Dawley rats. Zolpidem (5, 10 or 20 mg/kg, i.p.) or vehicle was administered twice daily, at the beginning and middle of the sleep period, for either 2 days (acute study) or 21 days (chronic study). Proliferation and cell survival were measured by staining for Ki67 or 5-bromo-2'-deoxyurdine (BrdU), respectively. Acute administration of zolpidem produced a suppression of cell proliferation, which attained statistical significance only in the aged animals. The magnitude of the suppressive effect was larger in the hilus than in the subgranular zone (SGZ). In contrast, chronic administration of zolpidem produced little or no effect on proliferation in either age group, despite marked differences in basal proliferation levels between the two age groups. Similarly, there was little change in cell survival following chronic zolpidem administration in young versus old animals. A slight reduction of cell survival in the granular cell layer (GCL)/SGZ was observed in young animals and a slight augmentation in aged animals. To the extent that zolpidem improves sleep, these data suggest little or no benefit of hypnotic drug treatment on neurogenesis parameters in young or old rats.

New neurons in the adult brain: the role of sleep and consequences of sleep loss.

Research over the last few decades has firmly established that new neurons are generated in selected areas of the adult mammalian brain, particularly the dentate gyrus of the hippocampal formation and the subventricular zone of the lateral ventricles. The function of adult-born neurons is still a matter of debate. In the case of the hippocampus, integration of new cells in to the existing neuronal circuitry may be involved in memory processes and the regulation of emotionality. In recent years, various studies have examined how the production of new cells and their development into neurons is affected by sleep and sleep loss. While disruption of sleep for a period shorter than one day appears to have little effect on the basal rate of cell proliferation, prolonged restriction or disruption of sleep may have cumulative effects leading to a major decrease in hippocampal cell proliferation, cell survival and neurogenesis. Importantly, while short sleep deprivation may not affect the basal rate of cell proliferation, one study in rats shows that even mild sleep restriction may interfere with the increase in neurogenesis that normally occurs with hippocampus-dependent learning. Since sleep deprivation also disturbs memory formation, these data suggest that promoting survival, maturation and integration of new cells may be an unexplored mechanism by which sleep supports learning and memory processes. Most methods of sleep deprivation that have been employed affect both non-rapid eye movement (NREM) and rapid eye movement (REM) sleep. Available data favor the hypothesis that decreases in cell proliferation are related to a reduction in REM sleep, whereas decreases in the number of cells that subsequently develop into adult neurons may be related to reductions in both NREM and REM sleep. The mechanisms by which sleep loss affects different aspects of adult neurogenesis are unknown. It has been proposed that adverse effects of sleep disruption may be mediated by stress and glucocorticoids. However, a number of studies clearly show that prolonged sleep loss can inhibit hippocampal neurogenesis independent of adrenal stress hormones. In conclusion, while modest sleep restriction may interfere with the enhancement of neurogenesis associated with learning processes, prolonged sleep disruption may even affect the basal rates of cell proliferation and neurogenesis. These effects of sleep loss may endanger hippocampal integrity, thereby leading to cognitive dysfunction and contributing to the development of mood disorders.

Age-dependent decline in hippocampal neurogenesis is not altered by chronic treatment with fluoxetine.

There has been ongoing controversy as to whether selective serotonin reuptake inhibitors (SSRIs) exhibit the same antidepressant efficacy and risk profile within different age groups. Although the etiology of such potential differences is currently not clear, age-dependent differences in the rate of hippocampal neurogenesis offer one possibility. In the current studies we have therefore examined whether fluoxetine, the prototypical selective serotonin reuptake inhibitor, differentially modulates neurogenesis in adolescent, young adult, and aged rats. Proliferation in the dentate gyrus was measured by assaying expression of the endogenous proliferative marker, Ki67. Survival of proliferating cells was assayed by staining with BrdU. We confirmed previous reports that the rate of neurogenesis, as well as the survival of proliferating cells, decreases significantly with age. Moderate decreases were found in young adult rats relative to adolescent rats, and profound decreases were found in aged rats. We additionally found that age did not alter the response to 25 days of treatment with fluoxetine. In fact, we did not observe enhancement of hippocampal neurogenesis, nor enhancement of proliferating cell survival, in any of the three age groups despite using doses of fluoxetine which have been reported to be effective. In addition to finding no age-dependent effects, our data question the general reproducibility of previously reported fluoxetine effects in animals.

The effect of prolonged anesthesia with isoflurane, propofol, dexmedetomidine, or ketamine on neural cell proliferation in the adult rat.

BACKGROUND: Recent evidence indicates that new neurons are produced in the adult hippocampus, and play a functional role in cognitive processes such as learning and memory. In animals, new neuron production is suppressed by increasing age, gamma-aminobutyric acid receptor activity, reductions in basal forebrain activity and brain norepinephrine levels, and decreased environmental stimuli. Similarities between these effects and those of anesthetic administration suggest that anesthetics may modulate new cell production, and raise the possibility that postoperative cognitive dysfunction may result, in part, from anesthetic-induced suppression of adult neurogenesis. To test this hypothesis, we investigated the effects of prolonged anesthesia with four different anesthetics on hippocampal cell proliferation in young and older rats. METHODS: Young (approximately 3 mo) and older, middle-aged (approximately 12 mo) male Sprague-Dawley rats received one of four anesthetics (propofol, isoflurane, dexmedetomidine, and ketamine) for 8 h. Rats breathed spontaneously, and anesthesia was titrated to loss of righting reflex and tolerance of clip-style pulse oximetry. Six hours into the anesthetic, rats received 200 mg/kg bromodeoxyuridine (BrdU) intraperitoneally and were killed hours later. Frozen hippocampal sections were collected and processed for BrdU using an immunoperoxidase technique. BrdU(+) cells in the dentate gyrus were then counted, and compared with unanesthetized controls to determine the degree of new cell production. All four anesthetics were given to young rats. Older rats received isoflurane and ketamine, and also received isoflurane during their dark phase. RESULTS: Forty-two young, and 26 older, middle-aged rats were studied. When compared with controls, prolonged anesthesia in young rats with any drug had no effect on the number of BrdU(+) cells. BrdU labeling was also unaffected in older rats given isoflurane for 8 h during the light phase. Older rats had significantly lower BrdU(+) cell counts than younger rats. In older rats, ketamine anesthesia reduced BrdU(+) cell counts by 26% when compared with unanesthetized controls. Older rats given isoflurane for 8 h during their dark phase demonstrated no difference in BrdU labeling when compared with unanesthetized controls. CONCLUSION: Despite using multiple, mechanistically distinct drugs, we found no effect of prolonged anesthesia on adult hippocampal cell proliferation in young rats, a slight suppressive effect of ketamine in older rats, and no circadian effect with isoflurane. These data indicate that anesthetics are unlikely to alter cell proliferation, and by extension that anesthetic-induced inhibition of cell proliferation is unlikely to play a major role in postoperative cognitive impairment. The contrast between our findings, current concepts of anesthetic action, and known modifiers of cell proliferation suggest an incomplete understanding of the pharmacological and behavioral factors governing new neuron production.

Delayed suppression of hippocampal cell proliferation in rats following inescapable shocks.

Adult Sprague-Dawley rats were exposed to a single session of 100 inescapable tail shocks (IS). Bromodeoxyuridine (BrdU) was administered 1 h, 2 days or 7 days later and hippocampal cell proliferation (CP) was assessed after a 2-h survival period. Measures of plasma corticosterone (CORT) levels were also obtained. Despite a large increase in CORT immediately following IS, no associated change in CP was observed. In fact, the only significant change in CP was seen 7 days after IS, at a time when CORT was unchanged from control levels. These data raise questions about the general nature of the relationship between CORT and CP. They also suggest that, under some conditions, changes in hippocampal CP may emerge only after an "incubation period".

Despite strong behavioral disruption, Delta9-tetrahydrocannabinol does not affect cell proliferation in the adult mouse dentate gyrus.

Marijuana is a widely abused illicit drug known to cause significant cognitive impairments. Marijuana has been hypothesized to target neurons in the hippocampus because of the abundance of cannabinoid receptors present in this structure. While there is no clear evidence of neuropathology in vivo, suppression of brain mitogenesis, and ultimately neurogenesis, may provide a sensitive index of marijuana's more subtle effects on neural mechanisms subserving cognitive functions. We examined the effects of different doses and treatment regimens of Delta(9)-tetrahydrocannabinol (THC), the main active ingredient in marijuana, on cell proliferation in the dentate gyrus of adult male mice. Following drug treatment, the thymidine analog 5-bromo-2'-deoxyuridine (BrdU; 200 mg/kg, i.p.) was administered two hours prior to sacrifice to assess cell proliferation, the first step in neurogenesis. Administration of THC produced dose-dependent catalepsy and suppression of motor activity. The number of BrdU-labeled cells was not significantly changed from vehicle control levels following either acute (1, 3, 10, 30 mg/kg, i.p.), sequential (two injections of 10 or 30 mg/kg, i.p., separated by 5 h), or chronic escalating (20 to 80 mg/kg, p.o.; for 3 weeks) drug administration. Furthermore, acute administration of the potent synthetic cannabinoid receptor agonist R-(+)-WIN 55,212-2 (WIN; 5 mg/kg, i.p.) also had no significant effect on cell proliferation. These findings provide no evidence for an effect of THC on hippocampal cell proliferation, even at doses producing gross behavioral intoxication. Whether marijuana or THC affects neurogenesis remains to be explored.

Circadian variation in mouse hippocampal cell proliferation.

Hippocampal cell proliferation and concomitant motor activity were examined in adult male mice (C57BL/6J) across a 12:12h light-dark cycle. 5-Bromo-2'-deoxyuridine (BrdU) (200 mg/kg, i.p.) was administered at six equally spaced time points across 24h. A significant change in cell proliferation was found in the hilus (light phase>dark phase), but not in the granule cell layer (GCL)/subgranular zone (SGZ). Since it is generally believed that proliferating cells in the hilus and GCL/SGZ give rise primarily to glia and neurons, respectively, these data suggest a possible circadian influence on gliogenesis, rather than neurogenesis.

Repeated brief social defeat episodes in mice: effects on cell proliferation in the dentate gyrus.

Stressful experiences can affect hippocampal structure and function and can suppress new cell birth in the adult hippocampus in several species. Here we examine how repeated intermittent social defeat affects cell proliferation in the dentate gyrus (DG) in mice. Adult male CFW mice were subjected to 10 daily social defeat episodes, 3 defeat episodes within one day or a single defeat episode. Intruder mice were injected with 5-bromo-2'-deoxyuridine (BrdU, 200mg/kg, i.p.) 1h after the last fight, and incorporation of BrdU into proliferating cells in the DG was quantified. In a third experiment, aggressive resident mice were allowed to fight with an intruder mouse every day for 10 days, and these residents were injected with BrdU 1h after the last aggressive encounter. There was a significant decrease in cell proliferation in mice that received 10 social defeats, confirming and extending earlier results. This decrease is correlated with the intensity of the defeat experiences, as quantified by frequency of attack bites. Cell proliferation was slightly inhibited after a single defeat, although this effect was not significant. Three defeats within a 5-h period had no effect on levels of proliferation. Offensive aggressive stress in the residents did not result in any changes in hippocampal cell proliferation. These data indicate that repeated intermittent social defeat experienced over multiple days suppresses proliferation in the DG, and this may have important implications for our understanding of hippocampal changes related to stress psychopathologies.

"Fatigue" of medullary but not mesencephalic raphe serotonergic neurons during locomotion in cats.

Single unit activity of presumed serotonergic neurons in the medulla [n. raphe obscurus (NRO) and pallidus (NRP)] or the mesencephalon [n. raphe dorsalis (DRN)] was recorded in adult male cats during prolonged treadmill locomotion. Treadmill speed was set at a moderate level (0.4 m/s) in order to induce long-duration locomotion. The typical time to "fatigue" (failure to keep pace, falling behind and reluctance to continue) was approximately 40 min in both groups, at which point cats typically displayed marked panting and vocalization. The activity of DRN neurons was unchanged from baseline during the locomotion trial and during the recovery phase. By contrast, the activity of NRO/NRP neurons decreased steadily across the locomotion trial, reaching a mean decrease of approximately 50% (during the first min after the treadmill was turned off). Full recovery of single unit activity to a level approximating the baseline discharge rate required 30-45 min. Possible mechanisms underlying these changes are discussed as is the role of serotonin and fatigue in human pathology.

Single-unit responses of serotonergic medullary raphe neurons to cardiovascular challenges in freely moving cats.

Single-unit activity of serotonergic neurons in the nuclei raphe obscurus (NRO) and raphe pallidus (NRP) were recorded in conjunction with heart rate in freely moving cats in response to systemic administration of vasoactive drugs and to graded haemorrhage. Bolus administration of phenylephrine hydrochloride and sodium nitroprusside (20 microg/kg, i.v.) produced a marked, transient reflex bradycardia (-42 b.p.m.) and tachycardia (+60 b.p.m.), respectively. The activity of NRO/NRP serotonergic neurons remained unchanged after phenylephrine and nitroprusside administration. The administration of hydralazine (1 mg/kg, i.v.), a long-acting vasodilator, produced sustained tachycardia (+60 b.p.m.), which was not accompanied by changes in neuronal activity, despite prolonged reflex activation of the sympathetic nervous system. The initial withdrawal of up to 15% of total blood volume increased heart rate (+12 b.p.m.), whereas the removal of 22.5% of total blood decreased heart rate (-44 b.p.m.). The activity of NRO/NRP serotonergic neurons remained unaltered throughout graded haemorrhage trials, despite the changes in sympathetic outflow. Thus, serotonergic NRO and NRP neurons appear to be insensitive to alterations in blood pressure and baroreceptor activity, and this lack of responsiveness does not support a specific role for these cells in cardiovascular regulation. Furthermore, these neurons do not appear to be involved in physiological mechanisms underlying alterations in autonomic outflow invoked by hypertension and hypotension. Taken within the context of our previous work, the present data suggest that medullary serotonergic neurons may modulate autonomic outflow, but only in relation to their primary role in motor control.

Effect of number of tailshocks on learned helplessness and activation of serotonergic and noradrenergic neurons in the rat.

Adult male albino rats were exposed to varying numbers of tailshocks (0, 10, 50 or 100). The following day, their escape latencies in a shuttlebox were measured in order to estimate the degree of learned helplessness (LH) produced by the varying number of shocks. Only the groups exposed to 50 or 100 shocks displayed evidence of LH. In a parallel experiment, c-fos activation was used to determine the degree of activation of raphe serotonergic neurons (FosIR+5-HT) and locus coeruleus (LC) noradrenergic neurons (FosIR+TH) produced by the same shock conditions. Compared to unhandled cage controls, all shock groups (0 shocks was a restrained group) significantly activated both raphe and LC neurons. The 50 and 100 shock groups had significantly higher degrees of activation of serotonergic neurons in the rostral raphe groups and the LC than the 0 and 10 shock groups. These data are consistent with the hypothesis that activation of rostral raphe serotonergic neurons and LC noradrenergic neurons beyond a certain threshold may be critical for the development of LH. The relevance of these results for elucidating the neural bases of psychopathology is discussed.

Inescapable shock activates serotonergic neurons in all raphe nuclei of rat.

Animal studies examining the effects of stress upon brain serotonergic neurons have not presented a clearcut and consistent picture. One stressor that has been shown to exert a consistently strong effect on serotonin release and c-fos activation in the dorsal raphe nucleus of rats is a series of inescapable electrical shocks. Using immunohistochemical double labeling for c-fos activation and serotonin, we examined the effects of delivering 100 inescapable tailshocks to rats on serotonergic neuronal activation throughout the brainstem raphe system. This stimulus exerted a consistent and strong activation of the entire midline brain stem system of serotonergic neurons. The implications of these findings for animal models of human psychopathology are discussed.

An adaptive drug infusion system.

BACKGROUND: In order to reduce the overall size and power consumption of ambulatory drug infusion systems, and to provide higher delivery accuracy, faster start-up, and more rapid occlusion detection, a non-contacting, low-power thermal time-of-flight technology has been used to provide a pressure-based miniature wearable drug infusion system that automatically compensates in real time for changes in pressure, viscosity, and flow path geometry. METHODS: Prototypes have been designed, built, and tested on the bench and on animals. RESULTS: For liquid volumes ranging from 30 nL to 100 microL, the measured accuracy and precision of delivery were better than 1%. Tests on 30-kg swine showed delivery within the study accuracy. CONCLUSIONS: The performance of the prototypes demonstrates that real-time compensation of flow variables provides significant performance improvements in therapeutic infusion.