Dorsal hippocampus to nucleus accumbens projections drive reinforcement via activation of accumbal dynorphin neurons.

The hippocampus is pivotal in integrating emotional processing, learning, memory, and reward-related behaviors. The dorsal hippocampus (dHPC) is particularly crucial for episodic, spatial, and associative memory, and has been shown to be necessary for context- and cue-associated reward behaviors. The nucleus accumbens (NAc), a central structure in the mesolimbic reward pathway, integrates the salience of aversive and rewarding stimuli. Despite extensive research on dHPC→NAc direct projections, their sufficiency in driving reinforcement and reward-related behavior remains to be determined. Our study establishes that activating excitatory neurons in the dHPC is sufficient to induce reinforcing behaviors through its direct projections to the dorso-medial subregion of the NAc shell (dmNAcSh). Notably, dynorphin-containing neurons specifically contribute to dHPC-driven reinforcing behavior, even though both dmNAcSh dynorphin- and enkephalin-containing neurons are activated with dHPC stimulation. Our findings unveil a pathway governing reinforcement, advancing our understanding of the hippocampal circuity's role in reward-seeking behaviors.

Sex Differences in the Role of CNIH3 on Spatial Memory and Synaptic Plasticity.

BACKGROUND: CNIH3 is an AMPA receptor (AMPAR) auxiliary protein prominently expressed in the dorsal hippocampus (dHPC), a region that plays a critical role in spatial memory and synaptic plasticity. However, the effects of CNIH3 on AMPAR-dependent synaptic function and behavior have not been investigated. METHODS: We assessed a gain-of-function model of Cnih3 overexpression in the dHPC and generated and characterized a line of Cnih3-/- C57BL/6 mice. We assessed spatial memory through behavioral assays, protein levels of AMPAR subunits and synaptic proteins by immunoblotting, and long-term potentiation in electrophysiological recordings. We also utilized a super-resolution imaging workflow, SEQUIN (Synaptic Evaluation and Quantification by Imaging of Nanostructure), for analysis of nanoscale synaptic connectivity in the dHPC. RESULTS: Overexpression of Cnih3 in the dHPC improved short-term spatial memory in female mice but not in male mice. Cnih3-/- female mice exhibited weakened short-term spatial memory, reduced dHPC synapse density, enhanced expression of calcium-impermeable AMPAR (GluA2-containing) subunits in synaptosomes, and attenuated long-term potentiation maintenance compared with Cnih3+/+ control mice; Cnih3-/- males were unaffected. Further investigation revealed that deficiencies in spatial memory and changes in AMPAR composition and synaptic plasticity were most pronounced during the metestrus phase of the estrous cycle in female Cnih3-/- mice. CONCLUSIONS: This study identified a novel effect of sex and estrous on CNIH3's role in spatial memory and synaptic plasticity. Manipulation of CNIH3 unmasked sexually dimorphic effects on spatial memory, synaptic function, AMPAR composition, and hippocampal plasticity. These findings reinforce the importance of considering sex as a biological variable in studies of memory and hippocampal synaptic function.

Pharmacophore-Based Design of Phenyl-[hydroxycyclohexyl] Cycloalkyl-Carboxamide Mitofusin Activators with Improved Neuronal Activity.

Mitochondrial fragmentation from defective fusion or unopposed fission contributes to many neurodegenerative diseases. Small molecule mitofusin activators reverse mitochondrial fragmentation in vitro, promising a novel therapeutic approach. The first-in-class mitofusin activator, 2, has a short plasma t1/2 and limited neurological system bioavailability, conferring "burst activation". Here, pharmacophore-based rational redesign generated analogues of 2 incorporating cycloalkyl linker groups. A cyclopropyl-containing linker, 5, improved plasma and brain t1/2, increased nervous system bioavailability, and prolonged neuron pharmacodynamic effects. Functional and single-crystal X-ray diffraction studies of stereoisomeric analogues of 5 containing sulfur as a "heavy atom", 14A and 14B, showed that 5 biological activity resides in the trans-R/R configuration, 5B. Structural analysis revealed stereoselective interactions of 5 associated with its mimicry of MFN2 Val372, Met376, and His380 side chains. Modification of murine ALS phenotypes in vitro and in vivo supports advancement of 5B for neurological conditions that may benefit from sustained mitofusin activation.

Neurotropic and modulatory effects of insulin-like growth factor II in Aplysia.

Insulin-like growth factor II (IGF2) enhances memory in rodents via the mannose-6-phosphate receptor (M6PR), but the underlying mechanisms remain poorly understood. We found that human IGF2 produces an enhancement of both synaptic transmission and neurite outgrowth in the marine mollusk Aplysia californica. These findings were unexpected since Aplysia lack the mammal-specific affinity between insulin-like ligands and M6PR. Surprisingly, this effect was observed in parallel with a suppression of neuronal excitability in a well-understood circuit that supports several temporally and mechanistically distinct forms of memory in the defensive withdrawal reflex, suggesting functional coordination between excitability and memory formation. We hypothesize that these effects represent behavioral adaptations to feeding that are mediated by the endogenous Aplysia insulin-like system. Indeed, the exogenous application of a single recombinant insulin-like peptide cloned from the Aplysia CNS cDNA replicated both the enhancement of synaptic transmission, the reduction of excitability, and promoted clearance of glucose from the hemolymph, a hallmark of bona fide insulin action.

A Neurobehavioral Approach to Addiction: Implications for the Opioid Epidemic and the Psychology of Addiction.

Two major questions about addictive behaviors need to be explained by any worthwhile neurobiological theory. First, why do people seek drugs in the first place? Second, why do some people who use drugs seem to eventually become unable to resist drug temptation and so become "addicted"? We will review the theories of addiction that address negative-reinforcement views of drug use (i.e., taking opioids to alleviate distress or withdrawal), positive-reinforcement views (i.e., taking drugs for euphoria), habit views (i.e., growth of automatic drug-use routines), incentive-sensitization views (i.e., growth of excessive "wanting" to take drugs as a result of dopamine-related sensitization), and cognitive-dysfunction views (i.e., impaired prefrontal top-down control), including those involving competing neurobehavioral decision systems (CNDS), and the role of the insula in modulating addictive drug craving. In the special case of opioids, particular attention is paid to whether their analgesic effects overlap with their reinforcing effects and whether the perceived low risk of taking legal medicinal opioids, which are often prescribed by a health professional, could play a role in the decision to use. Specifically, we will address the issue of predisposition or vulnerability to becoming addicted to drugs (i.e., the question of why some people who experiment with drugs develop an addiction, while others do not). Finally, we review attempts to develop novel therapeutic strategies and policy ideas that could help prevent opioid and other substance abuse.

Hepatitis C viral infection and imprisonment among Aboriginal and Torres Strait Islander and non-Indigenous people who inject drugs.

INTRODUCTION AND AIMS: An understanding of the relationship between hepatitis C viral (HCV) infection and contextual factors such as imprisonment may contribute to the development of targeted treatment and prevention programs. We examine the associations of imprisonment and drug dependence with lifetime exposure to HCV, and whether these associations differ for Aboriginal and Torres Strait Islander and non-Indigenous people who inject drugs. DESIGN AND METHODS: Respondent-driven sampling was used in major cities and 'peer recruitment' in regional towns of Queensland to obtain a community sample of people who injected drugs, which comprised 243 Indigenous and 227 non-Indigenous participants who had ever been tested for HCV. Data are cross-sectional. Two binary Poisson models were developed to examine associations for variables relating to imprisonment, Indigeneity and drug use history. RESULTS: Sharing needles and syringes in prison (adjusted risk ratio 1.25, 95% confidence interval 1.02-1.53) remained significantly associated with HCV infection after adjustment for Indigeneity, injecting drug use history and drug dependence. Opioid dependence and concurrent dependence on opioids and methamphetamine was also independently associated with HCV infection. DISCUSSION AND CONCLUSIONS: Sharing needles and syringes in prison is linked with HCV infection, for both Aboriginal and Torres Strait Islander and non-Indigenous people who inject drugs. Further development of treatment and prevention programs in prisons is required, with consideration of the role of opioid and methamphetamine dependence in HCV exposure.

Patterns of drug dependence in a Queensland (Australia) sample of Indigenous and non-Indigenous people who inject drugs.

INTRODUCTION AND AIMS: Despite over-representation of Indigenous Australians in sentinel studies of injecting drug use, little is known about relevant patterns of drug use and dependence. This study compares drug dependence and possible contributing factors in Indigenous and non-Indigenous Australians who inject drugs. DESIGN AND METHODS: Respondent-driven sampling was used in major cities and 'peer recruitment' in regional towns of Queensland to obtain a community sample of Indigenous (n = 282) and non-Indigenous (n = 267) injectors. Data are cross sectional. Multinomial models were developed for each group to examine types of dependence on injected drugs (no dependence, methamphetamine-dependent only, opioid-dependent only, dependent on methamphetamine and opioids). RESULTS: Around one-fifth of Indigenous and non-Indigenous injectors were dependent on both methamphetamine and opioids in the previous 12 months. Psychological distress was associated with dual dependence on these drugs for Indigenous [adjusted relative risk (ARR) 4.86, 95% confidence interval (CI) 2.08-11.34] and non-Indigenous (ARR 4.14, 95% CI 1.59-10.78) participants. Unemployment (ARR 8.98, 95% CI 2.25-35.82) and repeated (> once) incarceration as an adult (ARR 3.78, 95% CI 1.43-9.97) were associated with dual dependence for Indigenous participants only. Indigenous participants had high rates of alcohol dependence, except for those dependent on opioids only. DISCUSSION AND CONCLUSIONS: The drug dependence patterns of Indigenous and non-Indigenous people who inject drugs were similar, including the proportions dependent on both methamphetamine and opioids. However, for Indigenous injectors, there was a stronger association between drug dependence and contextual factors such as unemployment and incarceration. Expansion of treatment options and community-level programs may be required. [Smirnov A, Kemp R, Ward J, Henderson S, Williams S, Dev A, Najman J M. Patterns of drug dependence in a Queensland (Australia) sample of Indigenous and non-Indigenous people who inject drugs. Drug Alcohol Rev 2016;35:611-619].

Contextual signaling in cancer.

The formation and maintenance of an organism are highly dependent on the orderly control of cell growth, differentiation, death, and migration. These processes are tightly regulated by signaling cascades in which a limited number of molecules dictate these cellular events. While these signaling pathways are highly conserved across species and cell types, the functional outcomes that result from their engagement are specified by the context in which they are activated. Using the Neurofibromatosis type 1 (NF1) cancer predisposition syndrome as an illustrative platform, we discuss how NF1/RAS signaling can create functional diversity at multiple levels (molecular, cellular, tissue, and genetic/genomic). As such, the ability of related molecules (e.g., K-RAS, H-RAS) to activate distinct effectors, as well as cell type- and tissue-specific differences in molecular composition and effector engagement, generate numerous unique functional effects. These variations, coupled with a multitude of extracellular cues and genomic/genetic changes that each modify the innate signaling properties of the cell, enable precise control of cellular physiology in both health and disease. Understanding these contextual influences is important when trying to dissect the underlying pathogenic mechanisms of cancer relevant to molecularly-targeted therapeutics.

Differential modulation of repetitive firing and synchronous network activity in neocortical interneurons by inhibition of A-type K(+) channels and Ih.

GABAergic interneurons provide the main source of inhibition in the neocortex and are important in regulating neocortical network activity. In the presence 4-aminopyridine (4-AP), CNQX, and D-APV, large amplitude GABAA-receptor mediated depolarizing responses were observed in the neocortex. GABAergic networks are comprised of several types of interneurons, each with its own protein expression pattern, firing properties, and inhibitory role in network activity. Voltage-gated ion channels, especially A-type K(+) channels, differentially regulate passive membrane properties, action potential (AP) waveform, and repetitive firing properties in interneurons depending on their composition and localization. HCN channels are known modulators of pyramidal cell intrinsic excitability and excitatory network activity. Little information is available regarding how HCN channels functionally modulate excitability of individual interneurons and inhibitory networks. In this study, we examined the effect of 4-AP on intrinsic excitability of fast-spiking basket cells (FS-BCs) and Martinotti cells (MCs). 4-AP increased the duration of APs in both FS-BCs and MCs. The repetitive firing properties of MCs were differentially affected compared to FS-BCs. We also examined the effect of Ih inhibition on synchronous GABAergic depolarizations and synaptic integration of depolarizing IPSPs. ZD 7288 enhanced the amplitude and area of evoked GABAergic responses in both cell types. Similarly, the frequency and area of spontaneous GABAergic depolarizations in both FS-BCs and MCs were increased in presence of ZD 7288. Synaptic integration of IPSPs in MCs was significantly enhanced, but remained unaltered in FS-BCs. These results indicate that 4-AP differentially alters the firing properties of interneurons, suggesting MCs and FS-BCs may have unique roles in GABAergic network synchronization. Enhancement of GABAergic network synchronization by ZD 7288 suggests that HCN channels attenuate inhibitory network activity.

Markers of hepatitis B infection and immunity in patients attending Aboriginal community controlled health services.

OBJECTIVE: Hepatitis B virus (HBV) infection remains an important cause of morbidity and mortality in Aboriginal and Torres Strait Islander people, who have high rates of infection compared with non-Indigenous Australians. We aimed to increase the evidence base around HBV in Aboriginal and Torres Strait Islander people through an analysis of routine clinical encounter data. DESIGN: A cross-sectional study of de-identified records from electronic patient systems over 5 years (8 January 2009 to 11 July 2013). SETTING: Four Aboriginal community controlled health services. PARTICIPANTS: All patients attending for a clinical visit were included in the study. Hepatitis B testing records were included if at least one serological test for HBV was done. MAIN OUTCOME MEASURES: Percentage of clinical patients tested for hepatitis B, compliance with guidelines and serological status. RESULTS: A total of 2959 people aged 15-54 years were screened for HBV, representing 17.2% of all people with a clinical visit in the study period. A total of 865 Aboriginal patients were tested concurrently for hepatitis B surface antigen (HBsAg), hepatitis B core antibody and hepatitis B surface antibody. Of those, 352 (40.7%) were susceptible to HBV infection (95% CI, 37.4%-43.9%) and 34 (3.9%) had either an acute or chronic infection indicated by a positive HBsAg result (95% CI, 2.6%-5.2%). In 329 women with antenatal screening, six (1.8%) returned a positive HBsAg result (95% CI, 0.37%-3.28%). CONCLUSION: A substantial proportion of patients tested were susceptible to HBV, with a high percentage potentially infectious compared with the general population. High levels of active infection and susceptibility to infection suggest many opportunities for transmission and indicate the potential benefit of routine HBV testing and vaccination in this population.

Regulation of epileptiform discharges in rat neocortex by HCN channels.

Hyperpolarization-activated, cyclic nucleotide-gated, nonspecific cation (HCN) channels have a well-characterized role in regulation of cellular excitability and network activity. The role of these channels in control of epileptiform discharges is less thoroughly understood. This is especially pertinent given the altered HCN channel expression in epilepsy. We hypothesized that inhibition of HCN channels would enhance bicuculline-induced epileptiform discharges. Whole cell recordings were obtained from layer (L)2/3 and L5 pyramidal neurons and L1 and L5 GABAergic interneurons. In the presence of bicuculline (10 µM), HCN channel inhibition with ZD 7288 (20 µM) significantly increased the magnitude (defined as area) of evoked epileptiform events in both L2/3 and L5 neurons. We recorded activity associated with epileptiform discharges in L1 and L5 interneurons to test the hypothesis that HCN channels regulate excitatory synaptic inputs differently in interneurons versus pyramidal neurons. HCN channel inhibition increased the magnitude of epileptiform events in both L1 and L5 interneurons. The increased magnitude of epileptiform events in both pyramidal cells and interneurons was due to an increase in network activity, since holding cells at depolarized potentials under voltage-clamp conditions to minimize HCN channel opening did not prevent enhancement in the presence of ZD 7288. In neurons recorded with ZD 7288-containing pipettes, bath application of the noninactivating inward cationic current (Ih) antagonist still produced increases in epileptiform responses. These results show that epileptiform discharges in disinhibited rat neocortex are modulated by HCN channels.

Female preference for males depends on reproductive physiology in the African cichlid fish Astatotilapia burtoni.

Mate choice is fundamental to sexual selection, yet little is known about underlying physiological mechanisms that influence female mating decisions. We investigated the endocrine underpinnings of female mate choice in the African cichlid Astatotilapia burtoni, a non-seasonal breeder. In addition to profiling behavioral and hormonal changes across the female reproductive cycle, we tested two hypotheses regarding possible factors influencing female mate choice. We first asked whether female mate choice is influenced by male visual and/or chemical cues. A. burtoni females were housed for one full reproductive cycle in the center of a dichotomous choice apparatus with a large (attractive) or small (unattractive) conspecific male on either side. Females associated mostly with small, less attractive males, but on the day of spawning reversed their preference to large, attractive males, with whom they mated almost exclusively, although this choice depended on the relative amount of androgens released into the water by small males. We next asked whether male behavior or androgen levels change in relation to the stimulus females' reproductive state. We found that stimulus male aggression decreased and reproductive displays increased as the day of spawning approached. Moreover male testosterone levels changed throughout the females' reproductive cycle, with larger males releasing more testosterone into the water than small males. Our data suggest that female association in a dichotomous choice assay is only indicative of the actual mate choice on the day of spawning. Furthermore, we show that male behavior and hormone levels are dependent on the reproductive state of conspecific females.

Directional responding of C57BL/6J mice in the Morris water maze is influenced by visual and vestibular cues and is dependent on the anterior thalamic nuclei.

Recent findings indicate that rats navigate in spatial tasks such as the Morris water maze (MWM) using a local cue-based reference frame rather than a distal cue-based reference frame. Specifically, rats swim in a particular direction to a location relative to pool-based cues, rather than to an absolute location defined by room-based cues. Neural mechanisms supporting this bias in rodents for relative responding in spatial tasks are not yet understood. Anterior thalamic neurons discharge according to the current directional heading of the animal. The contribution of head direction (HD) cell activity to navigation has been difficult to elucidate. We found that male C57BL/6J mice trained for 4 or 7 d in the MWM exhibited an overwhelming preference for swimming in a direction relative to pool-based cues over absolute responding during a platform-less probe test. Rotation of extramaze cues caused a corresponding rotation of the direction mice swam during the probe test, suggesting that both pool- and room-based reference frames guide platform search. However, disorienting the mice before the probe test disturbed relative responding. Therefore, relative responding is guided by both internal and external cue sources. Selective inactivation of anterior thalamic nuclei (ATN) by microinfusion of muscimol or fluorophore-conjugated muscimol caused a near complete shift in preference from relative to absolute responding. Interestingly, inactivation of the dorsal CA1 region of the hippocampus did not affect relative responding. These data suggest that ATN, and HD cells therein, may guide relative responding in the MWM, a task considered by most to reflect hippocampal processing.