Cooperative synaptic and intrinsic plasticity in a disynaptic limbic circuit drive stress-induced anhedonia and passive coping in mice.

Stress promotes negative affective states, which include anhedonia and passive coping. While these features are in part mediated by neuroadaptations in brain reward circuitry, a comprehensive framework of how stress-induced negative affect may be encoded within key nodes of this circuit is lacking. Here, we show in a mouse model for stress-induced anhedonia and passive coping that these phenomena are associated with increased synaptic strength of ventral hippocampus (VH) excitatory synapses onto D1 medium spiny neurons (D1-MSNs) in the nucleus accumbens medial shell (NAcmSh), and with lateral hypothalamus (LH)-projecting D1-MSN hyperexcitability mediated by decreased inwardly rectifying potassium channel (IRK) function. Stress-induced negative affective states are prevented by depotentiation of VH to NAcmSh synapses, restoring Kir2.1 function in D1R-MSNs, or disrupting co-participation of these synaptic and intrinsic adaptations in D1-MSNs. In conclusion, our data provide strong evidence for a disynaptic pathway controlling maladaptive emotional behavior.

Lateral preoptic area neurons signal cocaine self-administration behaviors.

The lateral preoptic area is implicated in numerous aspects of substance use disorder. In particular, the lateral preoptic area is highly sensitive to the pharmacological properties of psychomotor stimulants, and its activity promotes drug-seeking in the face of punishment and reinstatement during abstinence. Despite the lateral preoptic area's complicity in substance use disorder, how precisely lateral preoptic area neurons signal the individual components of drug self-administration has not been ascertained. To bridge this gap, we examined how the firing of single lateral preoptic area neurons correlates with three discrete elements of cocaine self-administration: (1) drug-seeking (pre-response), (2) drug-taking (response) and (3) receipt of the cocaine infusion. A significant subset of lateral preoptic area neurons responded to each component with a mix of increases and decreases in firing-rate. A majority of these neurons signal the operant response with increases in spiking, though responses during the drug-seeking, taking and reciept windows were highly correlated.

Suvorexant, an orexin/hypocretin receptor antagonist, attenuates motivational and hedonic properties of cocaine.

Orexins ('hypocretins') are peptides produced by neurons of the hypothalamus that project to structures implicated in reward and emotion processing. Converging evidence demonstrates functional roles of orexin signaling in arousal, sleep/wakefulness and motivated behaviors for natural and drug rewards. Suvorexant, a dual orexin receptor antagonist, recently received approval from the US Food and Drug Administration to treat insomnia. In Experiment 1, rats self-administered cocaine under a progressive-ratio schedule of reinforcement and the effects of suvorexant on motivation to self-administer cocaine were measured. In Experiment 2, the effects of suvorexant on cocaine reward were assessed by using a place conditioning paradigm, and 50-kHz ultrasonic vocalizations were also recorded to track changes in hedonic reactivity to cocaine. To rule out potentially confounding effects of suvorexant-induced somnolence, locomotor activity was also measured. In Experiment 3, the effects of suvorexant on cocaine-evoked elevations in ventral striatal dopamine were examined. Data reveal that suvorexant (i) reduced the number of cocaine infusions earned during progressive-ratio self-administration; (ii) attenuated initial positive hedonic reactivity to cocaine and prevented cocaine place preference; (iii) did not affect cocaine-induced hyperlocomotion and (iv) reduced cocaine-induced elevations in extracellular ventral striatal dopamine. The present study examined the therapeutic potential of suvorexant in rodent models of cocaine use disorder. These results contribute toward a growing literature supporting therapeutic roles of orexin receptor antagonists in treating substance use disorders.

Comparing rewarding and reinforcing properties between 'bath salt' 3,4-methylenedioxypyrovalerone (MDPV) and cocaine using ultrasonic vocalizations in rats.

Abuse of synthetic psychostimulants like synthetic cathinones has risen in recent years. 3,4-Methylenedioxypyrovalerone (MDPV) is one such synthetic cathinone that demonstrates a mechanism of action similar to cocaine. Compared to cocaine, MDPV is more potent at blocking dopamine and norepinephrine reuptake and is readily self-administered by rodents. The present study compared the rewarding and reinforcing properties of MDPV and cocaine using systemic injection dose-response and self-administration models. Fifty kilohertz ultrasonic vocalizations (USVs) were recorded as an index of positive affect throughout experiments. In Experiment 1, MDPV and cocaine dose-dependently elicited 50-kHz USVs upon systemic injection, but MDPV increased USVs at greater rates and with greater persistence relative to cocaine. In Experiment 2, latency to begin MDPV self-administration was shorter than latency to begin cocaine self-administration, and self-administered MDPV elicited greater and more persistent rates of 50-kHz USVs versus cocaine. MDPV-elicited 50-kHz USVs were sustained over the course of drug load-up whereas cocaine-elicited USVs waned following initial infusions. Notably, we observed a robust presence of context-elicited 50-kHz USVs from both MDPV and cocaine self-administering rats. Collectively, these data suggest that MDPV has powerfully rewarding and reinforcing effects relative to cocaine at one-tenth doses. Consistent with prior work, we additionally interpret these data in supporting that MDPV has significant abuse risk based on its potency and subjectively positive effects. Future studies will be needed to better refine therapeutic strategies targeted at reducing the rewarding effects of cathinone analogs in efforts to ultimately reduce abuse liability.

Automated acoustic analysis of 50-kHz ultrasonic vocalizations using template matching and contour analysis.

Ultrasonic vocalizations are a useful tool for inferring affective states in the rat and have been incorporated in research paradigms modeling important human conditions. While the majority of studies report the quantity or rate of observed ultrasonic vocalizations, growing evidence suggests that critical data may be contained in the acoustic features of individual vocalizations. Thus, the goal of the present study was to develop and validate a method for measuring acoustic parameters of ultrasonic vocalizations that were collected using automatic template detection. Acoustic parameters derived using this method were found to be comparable to those collected using commercially available software.

Electrophysiological evidence of alterations to the nucleus accumbens and dorsolateral striatum during chronic cocaine self-administration.

As drug use becomes chronic, aberrant striatal processing contributes to the development of perseverative drug-taking behaviors. Two particular portions of the striatum, the nucleus accumbens (NAc) and the dorsolateral striatum (DLS), are known to undergo neurobiological changes from acute to chronic drug use. However, little is known about the exact progression of changes in functional striatal processing as drug intake persists. We sampled single-unit activity in the NAc and DLS throughout 24 daily sessions of chronic long-access cocaine self-administration, and longitudinally tracked firing rates (FR) specifically during the operant response, an upward vertical head movement. A total of 103 neurons were held longitudinally and immunohistochemically localised to either NAc Medial Shell (n = 29), NAc Core (n = 30), or DLS (n = 54). We modeled changes representative of each category as a whole. Results demonstrated that FRs of DLS Head Movement neurons were significantly increased relative to baseline during all sessions, while FRs of DLS Uncategorised neurons were significantly reduced relative to baseline during all sessions. NAc Shell neurons' FRs were also significantly decreased relative to baseline during all sessions while FRs of NAc Core neurons were reduced relative to baseline only during training days 1-18 but were not significantly reduced on the remaining sessions (19-24). The data suggest that all striatal subregions show changes in FR during the operant response relative to baseline, but longitudinal changes in response firing patterns were observed only in the NAc Core, suggesting that this region is particularly susceptible to plastic changes induced by abused drugs.

Rat ultrasonic vocalizations demonstrate that the motivation to contextually reinstate cocaine-seeking behavior does not necessarily involve a hedonic response.

Human self-reports often indicate that changes in mood are a major contributor to drug relapse. Still, arguments have been made that instances of drug-seeking following abstinence in animal models (i.e. relapse/reinstatement) may be outside of hedonic control. Therefore, the present study utilized ultrasonic vocalizations in the rat in order to evaluate affect during cocaine self-administration and contextual reinstatement of cocaine-seeking in a pre-clinical model of drug relapse (abstinence-reinstatement model). Results show that while subjects effectively reinstated drug-seeking (lever pressing) following 30 days of abstinence, and spontaneously recovered/reinstated drug-seeking following 60 days of abstinence, ultrasonic vocalizations did not increase over baseline levels during either reinstatement session. These results are consistent with previous results from our laboratory and current theories of addiction suggesting that cues that are weakly associated with drug consumption can motivate drug-seeking behavior that is outside of hedonic processing.

Haploinsufficiency of the Parkinson's disease gene synaptojanin1 is associated with abnormal responses to psychomotor stimulants and mesolimbic dopamine signaling.

The synaptojanin-1 (SYNJ1) gene is known to be important for dopamine-related disorders. Recent evidence has demonstrated that Synj1 deficient mice (Synj1 +/-) have impairments in dopaminergic synaptic vesicular recycling. However, less is known about how Synj1 deficits affect the mesolimbic system, reward processing, and motivated behavior. To examine the role of the Synj1 gene in motivated behavior, we subjected male and female Synj1 +/- and Synj1 +/+ mice to a battery of behavioral tests evaluating hedonic responses, effortful responding, and responses to psychomotor stimulants. We observed that Synj1 +/- mice exhibit few differences in reward processing and motivated behavior, with normal hedonic responses and motivated responding for sucrose. However, male but not female Synj1 +/- demonstrated an attenuated conditioned place preference for cocaine that could not be attributed to deficits in spatial memory. To further understand the dopamine signaling underlying the attenuated response to cocaine in these mutant mice, we recorded nucleus accumbens dopamine in response to cocaine and observed that Synj1 +/- male and female mice took longer to reach peak dopamine release following experimenter-administered cocaine. However, female mice also showed slower decay in accumbens dopamine that appear to be linked to differences in cocaine-induced DAT responses. These findings demonstrate that SYNJ1 deficiencies result in abnormal mesolimbic DA signaling which has not previously been demonstrated. Our work also highlights the need to develop targeted therapeutics capable of restoring deficits in DAT function, which may be effective for reversing the pathologies associated with Synj1 mutations.

Cognitive representations of intracranial self-stimulation of midbrain dopamine neurons depend on stimulation frequency.

Dopamine neurons in the ventral tegmental area support intracranial self-stimulation (ICSS), yet the cognitive representations underlying this phenomenon remain unclear. Here, 20-Hz stimulation of dopamine neurons, which approximates a physiologically relevant prediction error, was not sufficient to support ICSS beyond a continuously reinforced schedule and did not endow cues with a general or specific value. However, 50-Hz stimulation of dopamine neurons was sufficient to drive robust ICSS and was represented as a specific reward to motivate behavior. The frequency dependence of this effect is due to the rate (not the number) of action potentials produced by dopamine neurons, which differently modulates dopamine release downstream.

Maternal hypertensive disorders in pregnancy and self-reported cognitive impairment of the offspring 70 years later: the Helsinki Birth Cohort Study.

OBJECTIVE: We tested whether maternal hypertensive disorders during pregnancy predict self-reported cognitive impairment, which is one of the earliest behavioral markers of dementia, of the offspring 70 years later. STUDY DESIGN: We included 876 participants of the Helsinki Birth Cohort Study 1934-44 who were born after normotensive, preeclamptic, or hypertensive pregnancies that were defined by the use of the mother's blood pressure and urinary protein measurements at maternity clinics and birth hospitals. The participants completed a psychological questionnaire that included questions on cognitive failures and dysexecutive functioning at an average age of 69.3 ± 3.1 (SD) years. RESULTS: In comparison with the offspring who were born after normotensive pregnancies, the offspring who were born after preeclamptic pregnancies reported more frequent complaints of cognitive failures, distractibility, and false triggering. Further, among women we found maternal hypertension without proteinuria that was associated with more frequent complaints of cognitive failures, forgetfulness, and false triggering. CONCLUSION: Hypertensive disorders during pregnancy are associated with more frequent subjective complaints of cognitive failures of the offspring in old age.

The shape of the placental surface at birth and colorectal cancer in later life.

OBJECTIVES: Many chronic diseases, including certain cancers, may originate through variations in the supply of nutrients to the fetus. These variations change gene expression and permanently set the structure and function of the body, a process known as programming. Fetal nutrition depends on the mother's metabolism and nutritional reserves, and on the placenta's ability to transfer nutrients from mother to baby. In this study, we examine how colorectal cancer is related to maternal and placental characteristics. METHODS: We ascertained 275 cases of colorectal cancer among the 20,431 people in the Helsinki Birth Cohort, who were born during 1924-1944 and whose body size at birth was recorded, together with the shape and size of the placenta. RESULTS: Hazard ratios for colorectal cancer increased as the placental surface became longer and more oval. The hazard ratio was 2.3 (95% CI 1.2-4.7) among people in whom the difference between the length and breadth of the surface exceeded 6 cm, compared with those in whom there was no difference. Colorectal cancer was unrelated to other placental measurements or to body size at birth. CONCLUSION: An oval placental surface at birth is associated with later colorectal cancer. The shape of the placental surface is determined by events at around 8-12 weeks gestation. We speculate that, if the spiral arteries open prematurely, the surface becomes more oval and the fetus is at risk of oxidative damage at a time when the colon is differentiating.

The velocity of fetal growth is associated with the breadth of the placental surface, but not with the length.

OBJECTIVES: Studies of the placenta in pregnancies complicated by pre-eclampsia have led to the suggestion that tissue along the length and breadth of its surface has different functions. A recent study in Saudi Arabia showed that the body size of newborn babies was related to the breadth of the surface at birth but not to its length. We have now examined whether the association between placental breadth and body size reflects large size of the baby from an early stage of gestation or rapid growth between early and late gestation. METHODS: We studied 230 women who gave birth to singleton babies in King Khalid Hospital, Riyadh, Saudi Arabia. In total, 176 had ultrasound measurements both before 28 weeks and at 28 weeks or later, which we define as early and late gestation. We used these to calculate growth velocities between early and late gestation, which we expressed as the change in standard deviation scores over a 10-week period. RESULTS: The breadth of the placental surface was correlated with fetal growth velocity. The correlation coefficients were 0.24 (P = 0.002) for the head circumference, 0.24 (P = 0.001) for the biparietal diameter and 0.34 (P < 0.001) for the abdominal circumference. The length of the surface was not related to fetal growth velocity. CONCLUSIONS: Tissue along the breadth of the placental surface may be more important than tissue along the length in the transfer of nutrients from mother to baby. This may be part of a wider phenomenon of regional differences in function across the placental surface.

The developmental origins of chronic rheumatic heart disease.

OBJECTIVES: Programming is the phenomenon whereby the body's structures and functions are permanently set by nutrition and other influences during early development. There is increasing evidence that programming in utero initiates cardiovascular disease. We hypothesized that susceptibility to developing chronic rheumatic heart disease on exposure to Streptococcus pyogenes is programmed. METHODS: We studied hospital admissions and deaths from chronic rheumatic heart disease in 20,431 people born in Helsinki, Finland, during 1924-1944. One hundred and one people, 56 men, and 45 women, had chronic rheumatic heart disease. RESULTS: The disease was not associated with body or placental size at birth. It was, however, associated with a long umbilical cord so that the hazard ratio for the disease was 1.23 (95% CI 1.04-1.45, P = 0.02) for every 10 cm increase in cord length. This association was present in people with mitral valve disease, hazard ratio 1.5 (1.20-1.89, P < 0.0001), but not in people with aortic valve disease, hazard ratio 1.0 (0.76-1.33, P = 0.97). Growing up in large households increased the risk of rheumatic heart disease. CONCLUSION: Longer umbilical cords have more spirals and a greater density of spirals per unit of length. Increased spiraling will increase the resistance to flow and the pressure load on the fetal heart. This could affect the development of the heart's valves and make them more vulnerable to the autoimmune process initiated by Streptococcus pyogenes. The mitral valve may be more vulnerable than the aortic valve because the valve leaflets are larger and therefore have greater wall stress.

Foetal and childhood growth and asthma in adult life.

AIM: Recent research suggests that asthma may originate through defects in the airway epithelium, acquired in utero, and an altered response to infections after birth. Here, we examine whether asthma in adult life is associated with reduced body size at birth and poor living conditions in childhood. METHODS: We studied 658 people taking medication for asthma in a cohort of 13 345 men and women born in Helsinki, Finland, during 1934-1944. Their body and placental size at birth, and their living conditions and growth in childhood, had been recorded. RESULTS: The odds ratios for asthma were 0.93 (95% CI 0.89-0.97, p = 0.001) per cm increase in birth length and 0.92 (0.89-0.96, p < 0.001) per cm increase in the length of placental surface. After allowing for size at birth, growth during childhood was unrelated to asthma. People who were born into families of low socio-economic status were at increased risk of later asthma. CONCLUSION: Slow linear growth in utero, which could be a result of impaired placentation, increases the risk of later asthma. Slow linear growth may be associated with impaired development of the airways. Babies with impaired lung development born into families of low socio-economic status may be most vulnerable to the disease.

The obstetric origins of health for a lifetime.

There is a new "developmental" model for the origins of a wide range of chronic diseases. Under this model the causes to be identified are linked to normal variations in fetoplacental development. These variations are thought to lead to variations in the supply of nutrients to the baby that permanently alter gene expression, a process known as "programming." According to the developmental model variations in the processes of development program the function of a few key systems that are linked to disease, including the immune system, antioxidant defenses, inflammatory responses, and the number and quality of stem cells.

Neuropathic pain as a trigger for histone modifications in limbic circuitry.

Chronic pain involves both central and peripheral neuronal plasticity that encompasses changes in the brain, spinal cord, and peripheral nociceptors. Within the forebrain, mesocorticolimbic regions associated with emotional regulation have recently been shown to exhibit lasting gene expression changes in models of chronic pain. To better understand how such enduring transcriptional changes might be regulated within brain structures associated with processing of pain or affect, we examined epigenetic modifications involved with active or permissive transcriptional states (histone H3 lysine 4 mono and trimethylation, and histone H3 lysine 27 acetylation) in periaqueductal gray (PAG), lateral hypothalamus (LH), nucleus accumbens (NAc), and ventral tegmental area (VTA) 5 weeks after sciatic nerve injury in mice to model chronic pain. For both male and female mice in chronic pain, we observed an overall trend for a reduction of these epigenetic markers in periaqueductal gray, LH, and NAc, but not VTA. Moreover, we discovered that some epigenetic modifications exhibited changes associated with pain history, while others were associated with individual differences in pain sensitivity. When taken together, these results suggest that nerve injury leads to chronic chromatin-mediated suppression of transcription in key limbic brain structures and circuits, which may underlie enduring changes in pain processing and sensitivity within these systems.

Nucleus accumbens shell neurons' early sensitivity to cocaine is associated with future increases in drug intake.

The striatum, both dorsal and ventral, is strongly implicated in substance use disorder. Chronic consumption of abused substances, such as cocaine, can cause an oversaturation of mesostriatal dopamine, which results in alterations in the firing of striatal neurons. While most preclinical studies of drug self-administration (S-A) are focused on these alterations, individual differences in a subject's early responses to drugs can also account for substantial differences in addiction susceptibility. In this study, we modeled longitudinal pharmacokinetics using data from a previous longitudinal study (Coffey et al., 2015) and aimed to determine if firing in specific dorsal and ventral striatal subregions was subject to changes across chronic cocaine S-A, and if individual animal differences in striatal firing in response to early drug exposure correlated with increases in drug intake. We observed that the firing patterns of nucleus accumbens (NAc) core and shell neurons exhibited increasing sensitivity to cocaine over the first 6 S-A sessions and maintained a strong negative correlation between drug intake and neuronal firing rates across chronic S-A. Moreover, we observed that the early sensitivity of NAc shell neurons to cocaine correlated with future increases in drug intake. Specifically, rats whose NAc shell neurons were most inhibited by increasing levels of cocaine upon first exposure exhibited the strongest increases in cocaine intake over time. If this difference can be linked to a genetic difference, or druggable targets, it may be possible to screen for similar addiction susceptibility in humans or develop novel preemptive pharmacotherapies.

Cocaine-regulated trafficking of dopamine transporters in cultured neurons revealed by a pH sensitive reporter.

Cocaine acts by inhibiting plasma membrane dopamine transporter (DAT) function and altering its surface expression. The precise manner and mechanism by which cocaine regulates DAT trafficking, especially at neuronal processes, are poorly understood. In this study, we engineered and validated the use of DAT-pHluorin for studying DAT localization and its dynamic trafficking at neuronal processes of cultured mouse midbrain neurons. We demonstrate that unlike neuronal soma and dendrites, which contain a majority of the DATs in weakly acidic intracellular compartments, axonal DATs at both shafts and boutons are primarily (75%) localized to the plasma membrane, whereas large varicosities contain abundant intracellular DAT within acidic intracellular structures. We also demonstrate that cocaine exposure leads to a Synaptojanin1-sensitive DAT internalization process followed by membrane reinsertion that lasts for days. Thus, our study reveals the previously unknown dynamics and molecular regulation for cocaine-regulated DAT trafficking in neuronal processes.

Lateral preoptic area glutamate neurons relay nociceptive information to the ventral tegmental area.

The ventral tegmental area (VTA) has been proposed to play a role in pain, but the brain structures modulating VTA activity in response to nociceptive stimuli remain unclear. Here, we demonstrate that the lateral preoptic area (LPO) glutamate neurons relay nociceptive information to the VTA. These LPO glutamatergic neurons synapsing on VTA neurons respond to nociceptive stimulation and conditioned stimuli predicting nociceptive stimulation and also mediate aversion. In contrast, LPO GABA neurons synapsing in the VTA mediate reward. By ultrastructural quantitative synaptic analysis, ex vivo electrophysiology, and functional neuroanatomy we identify a complex circuitry between LPO glutamatergic and GABAergic neurons and VTA dopaminergic, GABAergic, and glutamatergic neurons. We conclude that LPO glutamatergic neurons play a causal role in the processing of nociceptive stimuli and in relaying information about nociceptive stimuli. The pathway from LPO glutamatergic neurons to the VTA represents an unpredicted interface between peripheral nociceptive information and the limbic system.

Cardiovascular morbidity and mortality in Finnish men and women separated temporarily from their parents in childhood--a life course study.

OBJECTIVE: Early-life stress may influence health later in life. We examined morbidity and mortality from cardiovascular disease over 60 years in individuals separated temporarily from their parents in childhood due to World War II. METHODS: We studied 12,915 members of the Helsinki Birth Cohort Study born from 1934 to 1944, of whom 1726 (13.4%) had been evacuated aboard without their parents to temporary foster families for an average of 1.8 (standard deviation = 1.1) years at an average age of 4.6 (standard deviation = 2.4) years. Data on parental separations were extracted from the Finnish National Archives. Information on use of medication for coronary heart disease and hypertension was derived from the National Register of Medication Reimbursement, and information on coronary events, stroke, and cardiovascular deaths was derived from Finnish Hospital Discharge Register and Causes of Death Register between Years 1971 and 2003. RESULTS: Participants who were separated in childhood used medications for coronary heart disease more frequently than those who were not separated (7.2% versus 4.5%, respectively; hazard ratio [HR] = 1.29, 95% confidence interval [CI] = 1.04-1.59; p = .02). No associations between separation and all-cause mortality (HR = 1.04, 95% CI = 0.90-1.20) or cardiovascular mortality (HR = 0.94, 95% CI = 0.72-1.21) or hospitalizations for cardiovascular disease or stroke were observed. CONCLUSIONS: Early-life stress may possibly be a factor predisposing to coronary heart disease decades later, but no evidence was found for increased risk of hospitalizations or mortality.