Withdrawal from cocaine conditioning progressively alters AMPA receptor-mediated transmission in the ventral hippocampus.

Drugs of abuse, such as cocaine, produce aberrant changes in synaptic transmission and plasticity that emerge throughout withdrawal. One region of the brain that displays a high degree of synaptic plasticity, as well as connectivity with mesolimbic structures such as the nucleus accumbens, is the ventral hippocampus (vH). Here, we investigated the effects of an escalating cocaine dosing schedule on vH CA1 excitatory transmission by measuring place preference and recording excitatory postsynaptic currents (EPSCs) at three different withdrawal time points: withdrawal day (WD) 2, 9 or 28. Behaviourally, this escalating cocaine-conditioning protocol was capable of producing conditioned place preference that persisted through WD28. Physiologically, cocaine conditioning produced an increase in vH excitatory transmission on WD2 that appeared to be the result of an increase in calcium-impermeable (CI)-AMPA receptor density. Excitatory transmission was still enhanced in cocaine-treated animals on WD9; however, a significant increase in the contribution of calcium-permeable (CP)-AMPA receptors to EPSCs was detected as compared with WD2. By WD28, these CP-AMPA receptors provided a major contribution to vH CA1 excitatory transmission, resulting in synaptic responses distinct from WD2 and WD9. Taken together, these results highlight progressive changes in vH synaptic transmission during withdrawal that may enhance cocaine contextual associations.

Dorsoventral-Specific Effects of Nerve Agent Surrogate Diisopropylfluorophosphate on Synaptic Transmission in the Mouse Hippocampus.

Although there has been an increasing appreciation for functional differences between the dorsal (dH) and ventral (vH) hippocampal sectors, there is a lack of information characterizing the cholinergic and noncholinergic mechanisms of acetylcholinesterase inhibitors on synaptic transmission along the hippocampal dorsoventral axis. Diisopropylfluorophosphate (DFP) is an organophosphate (OP) that is commonly employed as a nerve agent surrogate in vitro as well as in rodent models of disease states, such as Gulf War Illness. The present study investigated the cholinergic and noncholinergic mechanisms responsible for the effects of acute DFP exposure on dH and vH synaptic transmission in a hippocampal slice preparation. A paired-pulse extracellular recording protocol was used to monitor the population spike (PS) amplitude as well as the PS paired-pulse ratio (PS-PPR) in the CA1 subfield of the dH and the vH. We observed that DFP-induced PS1 inhibition was produced by a cholinergic mechanism in the dH, whereas a noncholinergic mechanism was indispensable in mediating the inhibitory effect of DFP on the PS1 in the vH. PS-PPR in both dH and vH sectors was increased by acute DFP exposure, an effect that was blocked by an N-methyl-D-aspartate receptor antagonist but not by cholinergic antagonists. Clinical reports have indicated dorsoventral-specific hippocampal abnormalities in cases of OP intoxications. Therefore, the observed dorsoventral-specific noncholinergic mechanisms underlying the effects of DFP on hippocampal synaptic transmission may have important implications for the treatment of OP overexposures. SIGNIFICANCE STATEMENT: It is unknown if acetylcholinesterase inhibitors differentially impact dorsal and ventral hippocampal synaptic transmission. The data in the present study show that an organophosphate, diisopropylfluorophosphate, impacts glutamatergic transmission along the dorsoventral axis in a hippocampal slice preparation via distinct cholinergic and noncholinergic mechanisms. These findings may provide insight into investigations of therapeutic agents that target noncholinergic mechanisms in cases of organophosphate overexposures.

Effects of high-fat diet and age on the blood lipidome and circulating endocannabinoids of female C57BL/6 mice.

Alterations in lipid metabolism play a significant role in the pathogenesis of obesity-associated disorders, and dysregulation of the lipidome across multiple diseases has prompted research to identify novel lipids indicative of disease progression. To address the significant gap in knowledge regarding the effect of age and diet on the blood lipidome, we used shotgun lipidomics with electrospray ionization-mass spectrometry (ESI-MS). We analyzed blood lipid profiles of female C57BL/6 mice following high-fat diet (HFD) and low-fat diet (LFD) consumption for short (6weeks), long (22weeks), and prolonged (36weeks) periods. We examined endocannabinoid levels, plasma esterase activity, liver homeostasis, and indices of glucose tolerance and insulin sensitivity to compare lipid alterations with metabolic dysregulation. Multivariate analysis indicated differences in dietary blood lipid profiles with the most notable differences after 6weeks along with robust alterations due to age. HFD altered phospholipids, fatty acyls, and glycerolipids. Endocannabinoid levels were affected in an age-dependent manner, while HFD increased plasma esterase activity at all time points, with the most pronounced effect at 6weeks. HFD-consumption also altered liver mRNA levels of PPARα, PPARγ, and CD36. These findings indicate an interaction between dietary fat consumption and aging with widespread effects on the lipidome, which may provide a basis for identification of female-specific obesity- and age-related lipid biomarkers.

Nutritional depletion of total mixed rations by red-winged blackbirds and projected impacts on dairy cow performance.

This Research Communication describes an investigation of the nutritional depletion of total mixed rations (TMR) by pest birds. We hypothesized that species-specific bird depredation of TMR can alter the nutritional composition of the ration and that these changes can negatively impact the performance of dairy cows. Blackbirds selected the high energy fraction of the TMR (i.e., flaked corn) and reduced starch, crude fat and total digestible nutrients during controlled feeding experiments. For Holsteins producing 37·1 kg of milk/d, dairy production modeling illustrated that total required net energy intake (NEI) was 35·8 Mcal/d. For the reference TMR unexposed to blackbirds and the blackbird-consumed TMR, NEI supplied was 41·2 and 37·8 Mcal/d, and the resulting energy balance was 5·4 and 2·0 Mcal/d, respectively. Thus, Holsteins fed the reference and blackbird-consumed TMR were estimated to gain one body condition score in 96 and 254 d, and experience daily weight change due to reserves of 1·1 and 0·4 kg/d, respectively. We discuss these results in context of an integrated pest management program for mitigating the depredation caused by pest birds at commercial dairies.

Cocaine self-administration induces changes in synaptic transmission and plasticity in ventral hippocampus.

Allowing rats extended access to cocaine self-administration is thought to recapitulate several key aspects of cocaine addiction in humans. Understanding the mechanisms that underlie drug-induced neuroadaptations that persist in the brain after protracted periods of abstinence is crucial towards the goal of developing therapeutic interventions for this disease state. We have employed both whole-cell voltage clamp and extracellular recording technique to assess changes in neurotransmission and long-term potentiation (LTP) in stratum radiatum of the CA1 region using the rat ventral hippocampal slice preparation. Rats allowed to self-administer cocaine daily, including 'long access' (6 hours) sessions, exhibited an increase in the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/N-methyl-d-aspartate current ratio and enhanced excitatory transmission following 3-5 weeks of abstinence. Inhibitory transmission was also significantly decreased in long-access animals, and the AMPA/N-methyl-d-aspartate ratio measured in the absence of GABAergic blockers was greatly enhanced. We also observed a significant reduction of LTP magnitude evoked in the long-access cocaine rats. These findings suggest the presence of synergistic effects of enhanced AMPA and diminished gamma-aminobutyric acid neurotransmission under physiological conditions in the CA1 region of cocaine-taking animals, supporting the conclusion that persisting enhancement of AMPA-mediated transmission and/or inhibition of gamma-aminobutyric acid-mediated transmission promoted a chronic state of potentiation that partially occluded further LTP. This increased output from the ventral hippocampus to other limbic areas would be among the drug-induced neuroadaptations that persist following abstinence from cocaine self-administration and therefore may contribute to the disease state of addiction.

Cyclin-Dependent Kinase Inhibitor 1a (p21) Modulates Response to Cocaine and Motivated Behaviors.

This study investigated the functional role of cyclin-dependent kinase inhibitor 1a (Cdkn1a or p21) in cocaine-induced responses using a knockout mouse model. Acute locomotor activity after cocaine administration (15 mg/kg, i.p.) was decreased in p21(-/-) mice, whereas cocaine-induced place preference was enhanced. Interestingly, κ-opioid-induced place aversion was also significantly enhanced. Concentration-dependent analysis of locomotor activity in response to cocaine demonstrated a rightward shift in the p21(-/-) mice. Pretreatment with a 5-hydroxytryptamine receptor antagonist did not alter the enhancement of cocaine-induced conditioned place preference in p21(-/-) mice, indicating a lack of involvement of serotonergic signaling in this response. Cocaine exposure increased p21 expression exclusively in the ventral sector of the hippocampus of rodents after either contingent or noncontingent drug administration. Increased p21 expression was accompanied by increased histone acetylation of the p21 promoter region in rats. Finally, increased neurogenesis in the dorsal hippocampus of p21(-/-) mice was also observed. These results show that functional loss of p21 altered the acute locomotor response to cocaine and the conditioned responses to either rewarding or aversive stimuli. Collectively, these findings demonstrate a previously unreported involvement of p21 in modulating responses to cocaine and in motivated behaviors.

Alterations in synaptic plasticity coincide with deficits in spatial working memory in presymptomatic 3xTg-AD mice.

Alzheimer's disease is a neurodegenerative condition believed to be initiated by production of amyloid-beta peptide, which leads to synaptic dysfunction and progressive memory loss. Using a mouse model of Alzheimer's disease (3xTg-AD), an 8-arm radial maze was employed to assess spatial working memory. Unexpectedly, the younger (3month old) 3xTg-AD mice were as impaired in the spatial working memory task as the older (8month old) 3xTg-AD mice when compared with age-matched NonTg control animals. Field potential recordings from the CA1 region of slices prepared from the ventral hippocampus were obtained to assess synaptic transmission and capability for synaptic plasticity. At 3months of age, the NMDA receptor-dependent component of LTP was reduced in 3xTg-AD mice. However, the magnitude of the non-NMDA receptor-dependent component of LTP was concomitantly increased, resulting in a similar amount of total LTP in 3xTg-AD and NonTg mice. At 8months of age, the NMDA receptor-dependent LTP was again reduced in 3xTg-AD mice, but now the non-NMDA receptor-dependent component was decreased as well, resulting in a significantly reduced total amount of LTP in 3xTg-AD compared with NonTg mice. Both 3 and 8month old 3xTg-AD mice exhibited reductions in paired-pulse facilitation and NMDA receptor-dependent LTP that coincided with the deficit in spatial working memory. The early presence of this cognitive impairment and the associated alterations in synaptic plasticity demonstrate that the onset of some behavioral and neurophysiological consequences can occur before the detectable presence of plaques and tangles in the 3xTg-AD mouse model of Alzheimer's disease.

Cocaine- or stress-induced metaplasticity of LTP in the dorsal and ventral hippocampus.

Despite the well documented role of the hippocampus in various modes of drug reinstatement behavior, the persisting effects of in vivo cocaine exposure on hippocampal synaptic plasticity are not sufficiently understood. In this report we investigated the effects of cocaine conditioning on long-term potentiation (LTP) in the CA1 region of hippocampus along its septotemporal axis. Male Sprague-Dawley rats experienced a behavioral protocol, in which locomotor activity was monitored in response to various conditioning treatments. LTP was measured in ex vivo slice preparations taken 1-2 weeks after the last behavioral session from the ventral (vH) and dorsal (dH) sectors of hippocampus. Unexpectedly, experiencing the minor intermittent stimuli of the behavioral protocol caused stress-induced metaplastic changes in both vH (increased LTP) and dH (decreased LTP) in the saline conditioned rats relative to behaviorally naïve controls. These stress effects in the vH and dH were blocked by conditioning with either mineralocorticoid (spironolactone) or glucocorticoid (mifepristone) antagonists, respectively. Stress-induced metaplasticity in the vH was also prevented by prior administration of the kappa opioid antagonist nor-binaltorphimine. Cocaine conditioning induced locomotor sensitization and significantly increased LTP in the vH without causing significant change in LTP in the dH. Cocaine-induced metaplasticity in the vH was prevented by co-administration of the dopamine D2-like antagonist eticlopride during cocaine conditioning, but not by co-administration of the D1/5 antagonist SCH 23390. Our results suggest that the functional connectivity of hippocampus is altered by metaplastic triggers such as exposure to drugs of abuse and/or stressors, thereby shifting the efferent output of hippocampus from dH (cortical) toward vH (limbic) influenced circuits.

A safe electric medical bed for an acute inpatient behavioral health care setting.

The purpose of this article is to describe the process of developing a safe electric bed for a traditional acute care adult behavioral health inpatient unit. Many articles and studies exist related to creating a safe environment on acute care psychiatric units, but very few address the use of electric hospital beds. The process of adapting a traditional electric bed for inpatient use by the nursing management team of the Behavioral Health Service at the University of Iowa Hospitals and Clinics is described, including specific safety features in the prototype bed. Policy changes during implementation and safety data after 12 months of bed use on the units are also presented. Results indicate that traditional electric hospital beds can be safely adapted for use on traditional acute care psychiatric units.

Vitamins and Trace Minerals in Ruminants: Confinement Feedlot.

Trace minerals and vitamins are essential for optimizing feedlot cattle growth, health, and carcass characteristics. Understanding factors that influence trace mineral and vitamin absorption and metabolism is important when formulating feedlot cattle diets. Current feedlot industry supplementation practices typically exceed published trace mineral requirements by a factor of 2 to 4. Therefore, the intent of this review is to briefly discuss the functions of trace minerals and vitamins that are typically supplemented in feedlot diets and to examine the impact of dose of trace mineral or vitamin on growth performance, health, and carcass characteristics of feedlot cattle.

Characterizing heat mitigation strategies utilized by beef processors in the United States.

During lairage at slaughter plants, cattle can be exposed to extreme heat conditions from pen densities and holding pen microclimates. While research outlining heat mitigation strategies used in other sectors of the beef supply chain is available, there is no published data on the use of heat mitigation strategies at slaughter plants. The objective of this study was to characterize short-term heat mitigation strategies used by commercial beef slaughter plants in the United States. Twenty-one beef slaughter plants, representing an estimated 60% of beef slaughter in the United States, were included in the study. All plants indicated use of at least one heat mitigation strategy, and five of them used more than one type. Sprinklers/misters were the most commonly used heat mitigation type (n = 17, 81%), and fans were the least common type (n = 4, 19%). Shade usage was present in several plants (n = 7, 33%), ranging from barn style roofs to shade cloths. Respondents indicated that they believed heat mitigation strategies provide benefits both to cattle well-being and meat quality outcomes. Future research should focus on the effectiveness of these techniques in improving animal well-being and quality outcomes in the slaughter plant environment and protocols for optimum implementation.

Evaluation of delayed LNFPIII treatment initiation protocol on improving long-term behavioral and neuroinflammatory pathology in a mouse model of Gulf War Illness.

Chemical overexposures and war-related stress during the 1990-1991 Gulf War (GW) are implicated in the persisting pathological symptoms that many GW veterans continue to endure. These symptoms culminate into a disease known as Gulf War Illness (GWI) and affect about a third of the GW veteran population. Currently, comprehensive effective GWI treatment options are unavailable. Here, an established GWI mouse model was utilized to explore the (1) long-term behavioral and neuroinflammatory effects of deployment-related GWI chemicals exposure and (2) ability of the immunotherapeutic lacto-N-fucopentaose III (LNFPIII) to improve deficits when given months after the end of exposure. Male C57BL6/J mice (8-9 weeks old) were administered pyridostigmine bromide (PB) and DEET for 14 days along with corticosterone (CORT; latter 7 days) to emulate wartime stress. On day 15, a single injection of the nerve agent surrogate diisopropylfluorophosphate (DFP) was given. LNFPIII treatment began 7 months post GWI chemicals exposure and continued until study completion. A battery of behavioral tests for assessment of cognition/memory, mood, and motor function in rodents was performed beginning 8 months after exposure termination and was then followed by immunohistochemcal evaluation of neuroinflammation and neurogenesis. Within tests of motor function, prior GWI chemical exposure led to hyperactivity, impaired sensorimotor function, and altered gait. LNFPIII attenuated these motor-related deficits and improved overall grip strength. GWI mice also exhibited more anxiety-like behavior that was reduced by LNFPIII; this was test-specific. Short-term, but not long-term memory, was impaired by prior GWI exposure; LNFPIII improved this measure. In the brains of GWI mice, but not in mice treated with LNFPIII, glial activation was increased. Overall, it appears that months after exposure to GWI chemicals, behavioral deficits and neuroinflammation are present. Many of these deficits were attenuated by LNFPIII when treatment began long after GWI chemical exposure termination, highlighting its therapeutic potential for veterans with GWI.

Transgenic mouse model for the formation of Hirano bodies.

BACKGROUND: Hirano bodies are actin-rich cytoplasmic inclusions found predominantly in the brain in association with a variety of conditions including aging and Alzheimer's disease. The function of Hirano bodies in normal aging and in progression of disease has not been extensively investigated due to a lack of experimental model systems. We have developed a transgenic mouse model by expression of a gain-of-function actin cross-linking protein mutant. RESULTS: We used the Cre/loxP system to permit tissue specific expression of Hirano bodies, and employed the murine Thy 1 promoter to drive expression of Cre recombinase in the brain. Hirano bodies were observed in the cerebral cortex and hippocampus of homozygous double transgenic 6 month old mice containing Cre. The Hirano bodies were eosinophilic rods, and also exhibited the paracrystalline F-actin filament organization that is characteristic of these inclusions. Mice with Hirano bodies appear healthy and fertile, but exhibited some alterations in both short-term and long-term synaptic plasticity, including paired-pulse depression rather than facilitation, and decreased magnitude of early LTP. CONCLUSIONS: Hirano bodies are not lethal and appear to have little or no effect on histology and tissue organization. Hirano bodies do modulate synaptic plasticity and exert clearly discernable effects on LTP and paired-pulse paradigms. This model system will allow us to investigate the impact of Hirano bodies in vivo, the pathways for formation and degradation of Hirano bodies, and whether Hirano bodies promote or modulate development of pathology and disease progression.

Influence of Molybdenum in Drinking Water or Feed on Copper Metabolism in Cattle-A Review.

The majority of Mo research has focused on the antagonist effect of Mo, alone or in combination with elevated dietary S, on Cu absorption and metabolism in ruminants. Diets containing both >5.0 mg of Mo/kg DM and >0.33% S have been reported to reduce the Cu status in cattle and sheep. Therefore, due to the potential for inducing Cu deficiency, Mo and S concentrations in the diet should be monitored and kept within appropriate values. Elevated sulfate concentrations in drinking water can also be detrimental to livestock production, especially in ruminants. High concentrations of sulfate in water have been extensively studied in cattle because high-sulfate water induces polioencephalomalacia in ruminants. However, little research has been conducted investigating the impact of Mo in water on Cu metabolism in ruminants. Based on the limited number of published experiments, it appears that Mo in drinking water may have a lower antagonistic impact on the Cu status in cattle when compared to Mo consumed in the diet. This response may be due to a certain percentage of water bypassing the rumen when consumed by ruminants. Therefore, the objective of this review was to examine the impact of Mo in drinking water on cattle performance and Mo and Cu metabolism.

Trace mineral source impacts rumen trace mineral metabolism and fiber digestion in steers fed a medium-quality grass hay diet.

Twelve Angus steers (BW 452.8 ± 6.1 kg) fitted with ruminal cannulae were used to determine the impact of trace mineral (TM) source on digestibility, ruminal volatile fatty acid (VFA) composition, ruminal soluble concentrations of Cu, Zn, and Mn, and relative binding strength of trace minerals located in the rumen insoluble digesta fraction. Steers were fed a medium-quality grass hay diet (DM basis: 10.8% CP, 63.1% neutral detergent fiber [NDF], 6.9 mg Cu/kg, 65.5 mg Mn/kg, and 39.4 mg Zn/kg) supplemented with protein for 21 d. Treatments consisted of either sulfate (STM) or hydroxy (HTM) sources (n = 6 steers/treatment) to provide 20, 40, and 60 mg supplemental Cu, Mn, and Zn/kg DM, respectively. Following a 21-d adaptation period, total fecal output was collected for 5 d. Dry matter (P < 0.07) and CP (P < 0.06) digestibility tended to be reduced, and NDF (P < 0.04) and acid detergent fiber (ADF) (P < 0.05) digestibility were reduced in STM- vs. HTM-supplemented steers. On day 6, ruminal fluid was collected at 0, 2, and 4 h post-feeding and analyzed for VFA. There were no treatment x time interactions for VFA. Steers receiving HTM had less (P < 0.02) molar proportions of butyric acid and greater (P < 0.05) total VFA concentrations than STM-supplemented steers. Steers were then fed the same diet without supplemental Cu, Zn, or Mn for 14 d. On day 15 steers received a pulse dose of 20 mg Cu, 40 mg Mn, and 60 mg Zn/kg DM from either STM or HTM (n = 6 steers/treatment). Ruminal samples were obtained at 2-h intervals starting at -4 and ending at 24 h relative to dosing. There was a treatment x time interaction (P < 0.03) for ruminal soluble Cu, Mn, and Zn concentrations. Ruminal soluble mineral concentrations were greater (P < 0.05) for Cu at 4, 6, 8, 10, 12, and 14 h; for Mn at 4 and 6 h; and for Zn at 4, 6, and 8 h post-dosing in STM compared with HTM-supplemented steers. Copper concentrations were greater (P < 0.05) at 12 and 24 h and Zn concentrations in ruminal solid digesta were greater at 24 h in HTM-supplemented steers. Upon dialysis against Tris-EDTA, the percent Zn released from digesta was greater (P < 0.05) at 12 h (P < 0.03) and 24 h (P < 0.05), and the percent Cu released was greater (P < 0.02) at 24 h post-dosing in HTM steers when compared with STM-supplemented steers. Results indicate that Cu and Zn from HTM have low solubility in the rumen and appear to be less tightly bound to ruminal solid digesta than Cu and Zn from STM. The lower ruminal soluble concentrations of Cu and Zn in steers given HTM were associated with greater fiber digestibility.

Impacts of shade on cattle well-being in the beef supply chain.

Shade is a mechanism to reduce heat load providing cattle with an environment supportive of their welfare needs. Although heat stress has been extensively reviewed, researched, and addressed in dairy production systems, it has not been investigated in the same manner in the beef cattle supply chain. Like all animals, beef cattle are susceptible to heat stress if they are unable to dissipate heat during times of elevated ambient temperatures. There are many factors that impact heat stress susceptibility in beef cattle throughout the different supply chain sectors, many of which relate to the production system, that is, availability of shade, microclimate of environment, and nutrition management. The results from studies evaluating the effects of shade on production and welfare are difficult to compare due to variation in structural design, construction materials used, height, shape, and area of shade provided. Additionally, depending on operation location, shade may or may not be beneficial during all times of the year, which can influence the decision to make shade a permanent part of management systems. Shade has been shown to lessen the physiologic response of cattle to heat stress. Shaded cattle exhibit lower respiration rates, body temperatures, and panting scores compared with unshaded cattle in weather that increases the risk of heat stress. Results from studies investigating the provision of shade indicate that cattle seek shade in hot weather. The impact of shade on behavioral patterns is inconsistent in the current body of research, with some studies indicating that shade provision impacts behavior and other studies reporting no difference between shaded and unshaded groups. Analysis of performance and carcass characteristics across feedlot studies demonstrated that shaded cattle had increased ADG, improved feed efficiency, HCW, and dressing percentage when compared with cattle without shade. Despite the documented benefits of shade, current industry statistics, although severely limited in scope, indicate low shade implementation rates in feedlots and data in other supply chain sectors do not exist. Industry guidelines and third-party on-farm certification programs articulate the critical need for protection from extreme weather but are not consistent in providing specific recommendations and requirements. Future efforts should include: updated economic analyses of cost vs. benefit of shade implementation, exploration of producer perspectives and needs relative to shade, consideration of shade impacts in the cow-calf and slaughter plant segments of the supply chain, and integration of indicators of affective (mental) state and preference in research studies to enhance the holistic assessment of cattle welfare.

Lacto-N-fucopentaose-III ameliorates acute and persisting hippocampal synaptic plasticity and transmission deficits in a Gulf War Illness mouse model.

AIMS: The present study investigated if treatment with the immunotherapeutic, lacto-N-fucopentaose-III (LNFPIII), resulted in amelioration of acute and persisting deficits in synaptic plasticity and transmission as well as trophic factor expression along the hippocampal dorsoventral axis in a mouse model of Gulf War Illness (GWI). MAIN METHODS: Mice received either coadministered or delayed LNFPIII treatment throughout or following, respectively, exposure to a 15-day GWI induction paradigm. Subsets of animals were subsequently sacrificed 48 h, seven months, or 11 months post GWI-related (GWIR) exposure for hippocampal qPCR or in vitro electrophysiology experiments. KEY FINDINGS: Progressively worsened impairments in hippocampal synaptic plasticity, as well as a biphasic effect on hippocampal synaptic transmission, were detected in GWIR-exposed animals. Dorsoventral-specific impairments in hippocampal synaptic responses became more pronounced over time, particularly in the dorsal hippocampus. Notably, delayed LNFPIII treatment ameliorated GWI-related aberrations in hippocampal synaptic plasticity and transmission seven and 11 months post-exposure, an effect that was consistent with enhanced hippocampal trophic factor expression and absence of increased interleukin 6 (IL-6) in animals treated with LNFPIII. SIGNIFICANCE: Approximately a third of Gulf War Veterans have GWI; however, GWI therapeutics are presently limited to targeted and symptomatic treatments. As increasing evidence underscores the substantial role of persisting neuroimmune dysfunction in GWI, efficacious neuroactive immunotherapeutics hold substantial promise in yielding GWI remission. The findings in the present report indicate that LNFPIII may be an efficacious candidate for ameliorating persisting neurological abnormalities presented in GWI.

Delayed treatment with the immunotherapeutic LNFPIII ameliorates multiple neurological deficits in a pesticide-nerve agent prophylactic mouse model of Gulf War Illness.

Residual effects of the 1990-1991 Gulf War (GW) still plague veterans 30 years later as Gulf War Illness (GWI). Thought to stem mostly from deployment-related chemical overexposures, GWI is a disease with multiple neurological symptoms with likely immunological underpinnings. Currently, GWI remains untreatable, and the long-term neurological disease manifestation is not characterized fully. The present study sought to expand and evaluate the long-term implications of prior GW chemicals exposure on neurological function 6-8 months post GWI-like symptomatology induction. Additionally, the beneficial effects of delayed treatment with the glycan immunotherapeutic lacto-N-fucopentaose III (LNFPIII) were evaluated. Male C57BL/6J mice underwent a 10-day combinational exposure (i.p.) to GW chemicals, the nerve agent prophylactic pyridostigmine bromide (PB) and the insecticide permethrin (PM; 0.7 and 200 mg/kg, respectively). Beginning 4 months after PB/PM exposure, a subset of the mice were treated twice a week until study completion with LNFPIII. Evaluation of cognition/memory, motor function, and mood was performed beginning 1 month after LNFPIII treatment initiation. Prior exposure to PB/PM produced multiple locomotor, neuromuscular, and sensorimotor deficits across several motor tests. Subtle anxiety-like behavior was also present in PB/PM mice in mood tests. Further, PB/PM-exposed mice learned at a slower rate, mostly during early phases of the learning and memory tests employed. LNFPIII treatment restored or improved many of these behaviors, particularly in motor and cognition/memory domains. Electrophysiology data collected from hippocampal slices 8 months post PB/PM exposure revealed modest aberrations in basal synaptic transmission and long-term potentiation in the dorsal or ventral hippocampus that were improved by LNFPIII treatment. Immunohistochemical analysis of tyrosine hydroxylase (TH), a dopaminergic marker, did not detect major PB/PM effects along the nigrostriatal pathway, but LNFPIII increased striatal TH. Additionally, neuroinflammatory cells were increased in PB/PM mice, an effect reduced by LNFPIII. Collectively, long-term neurobehavioral and neurobiological dysfunction associated with prior PB/PM exposure was characterized; delayed LNFPIII treatment provided multiple behavioral and biological beneficial effects in the context of GWI, highlighting its potential as a GWI therapeutic.

Lacto-N-fucopentaose-III (LNFPIII) ameliorates acute aberrations in hippocampal synaptic transmission in a Gulf War Illness animal model.

Approximately one-third of Persian Gulf War veterans are afflicted by Gulf War Illness (GWI), a chronic multisymptom condition that fundamentally presents with cognitive deficits (i.e., learning and memory impairments) and neuroimmune dysfunction (i.e., inflammation). Factors associated with GWI include overexposures to neurotoxic pesticides and nerve agent prophylactics such as permethrin (PM) and pyridostigmine bromide (PB), respectively. GWI-related neurological impairments associated with PB-PM overexposures have been recapitulated in animal models; however, there is a paucity of studies assessing PB-PM-related aberrations in hippocampal synaptic plasticity and transmission that may underlie behavioral impairments. Importantly, FDA-approved neuroactive treatments are currently unavailable for GWI. In the present study, we assessed the efficacy of an immunomodulatory therapeutic, lacto-N-fucopentaose-III (LNFPIII), on ameliorating acute effects of in vivo PB-PM exposure on synaptic plasticity and transmission as well as trophic factor/cytokine expression along the hippocampal dorsoventral axis. PB-PM exposure resulted in hippocampal synaptic transmission deficits 48 h post-exposure, a response that was ameliorated by LNFPIII coadministration, particularly in the dorsal hippocampus (dH). LNFPIII coadministration also enhanced synaptic transmission in the dH and the ventral hippocampus (vH). Notably, LNFPIII coadministration elevated long-term potentiation in the dH. Further, PB-PM exposure and LNFPIII coadministration uniquely altered key inflammatory cytokine and trophic factor production in the dH and the vH. Collectively, these findings demonstrate that PB-PM exposure impaired hippocampal synaptic responses 48 h post-exposure, impairments that differentially manifested along the dorsoventral axis. Importantly, LNFPIII ameliorated GWI-related electrophysiological deficits, a beneficial effect indicating the potential efficacy of LNFPIII for treating GWI.

Cocaine enhancement of long-term potentiation in the CA1 region of rat hippocampus: lamina-specific mechanisms of action.

There is an expanding body of work characterizing dopaminergic modulation of synaptic plasticity in the hippocampus CA1 region, an area known to be involved in learning and memory. However, in vitro studies to date have focused almost exclusively on the proximal and distal apical dendritic layers (strata radiatum and lacunosum moleculare, respectively). In this report, we establish that dopaminergic activity can enhance long-term potentiation (LTP) in the basal dendritic layer (stratum oriens) of CA1 in the rat hippocampal slice preparation. Application of the D(1/5) agonist SKF38393 (20 microM) significantly increased the magnitude of basal LTP of the fEPSP response following high-frequency stimulation of the Schaffer collateral/commissural inputs in the stratum oriens layer. In addition, endogenous dopamine (DA) activity facilitated by the presence of cocaine (6 muM) was also capable of enhancing the magnitude of basal LTP. Prior application of the D(1/5) antagonist SKF83566 (2 muM) prevented this effect of cocaine, indicating that endogenously released dopamine was exerting its LTP-enhancing effect in stratum oriens via activation of D(1/5) receptors. This final result stands in contrast with the previously characterized effects of cocaine on apical LTP in the stratum radiatum, which instead have been shown to require D(3) receptor activation. These observations demonstrate that dopaminergic mechanisms resulting in the enhancement of hippocampal LTP are lamina specific at Schaffer collateral/commissural synapses in the CA1 region. Synapse 2010. (c) 2010 Wiley-Liss, Inc.