Behavioural effects in mice orally exposed to domoic acid or ibotenic acid are influenced by developmental stages and sex differences.

The structure of the brain is dramatically altered during the critical period. Physiological substances (neurotransmitters, hormones, etc.) in the body fluctuate significantly before and after sexual maturation. Therefore, the effect of chemical exposure on the central nervous system often differs depending on the developmental stage and sex. We aimed to compare the behavioural effects that emerged from the administration of chemicals to mice of different life stages (immature or mature) and different sex (male or female). We administered mice with domoic acid (DA), a marine poison, and ibotenic acid (IA), found in poisonous mushrooms. These excitatory amino acids act as agonists for glutamate and are potent neurotoxins. Interestingly, the behavioural effects of these chemicals were completely different. Following DA administration, we observed memory deficits only in groups of male mice treated at maturity. Following IA administration, we observed deviations in emotional behaviour in groups of male mice treated at both immaturity and maturity. In contrast, few characteristic changes were detected in all groups of females. Our results support the theory that the behavioural effects of chemical administration vary considerably with developmental stages and sex. In conclusion, our findings promote better understanding of individual differences in excitatory chemical-induced neurotoxicity and provide evidence for future risk strategies and treatments.

Restricted lesions of the ventrolateral or dorsal columns of the periaqueductal gray promotes distinct effects on tonic immobility and defensive analgesia in guinea pigs.

Tonic immobility (TI) is an innate defensive response exhibited by prey when physical contact with a predator is prolonged and inescapable. This defensive response is able to activate analgesia mechanisms; this activation has adaptive value because, during an attack by a predator, the manifestation of recuperative behaviors can affect the appropriate behavioral defense strategy. Some studies have suggested that similar structures of the central nervous system can regulate the response of both TI and nociception. Thus, this study evaluated the effect of chemical lesion through the administration of ibotenic acid in restricted brain areas of the periaqueductal gray matter (PAG) in guinea pig on the TI response and nociception evaluated in the hot plate test before and after emission of TI. The data showed that an irreversible chemical lesion in the ventrolateral PAG reduced of the TI response as well as defensive antinociception. However, a lesion in the dorsal PAG blocked the defensive antinociception induced by TI but did not alter TI duration. In summary, one could hypothesize that the neural substrates responsible for defensive behavior and antinociception represent similar systems that are distinct in modulation. Thus, the ventrolateral PAG has been associated with the modulation of TI and the defensive antinociception induced by TI. In contrast, the integrity of the dorsal PAG should be necessary for defensive antinociception to occur but not to elicit TI behavior in guinea pigs.

Neurotoxic lesions of the pedunculopontine tegmental nucleus impair the elaboration of postictal antinociception.

Generalised tonic-clonic seizures, generated by abnormal neuronal hyper-activity, cause a significant and long-lasting increase in the nociceptive threshold. The pedunculopontine tegmental nucleus (PPTN) plays a crucial role in the regulation of seizures as well as the modulation of pain, but its role in postictal antinociceptive processes remains unclear. In the present study, we aimed to investigate the involvement of PPTN neurons in the postictal antinociception. Wistar rats had their tail-flick baseline recorded and were injected with ibotenic acid (1.0 µg/0.2 µL) into the PPTN, aiming to promote a local neurotoxic lesion. Five days after the neuronal damage, pentylenetetrazole (PTZ; 64 mg/kg) was intraperitoneally administered to induce tonic-clonic seizures. The tail-withdrawal latency was measured immediately after the seizures (0 min) and subsequently at 10-min intervals until 130 min after the seizures were induced pharmacologically. Ibotenic acid microinjected into the PPTN did not reduce the PTZ-induced seizure duration and severity, but it diminished the postictal antinociception from 0 to 130 min after the end of the PTZ-induced tonic-clonic seizures. These results suggest that the postictal antinociception depends on the PPTN neuronal cells integrity.

Parkinsonism and dystonia are differentially induced by modulation of different territories in the basal ganglia.

Numerous clinical and experimental observations suggest that deficient neuronal signaling in the globus pallidus externa (GPe) is integral to both Parkinson's disease (PD) and dystonia. In our previous studies in jaundiced dystonic rats, widespread silencing of neurons in GP (rodent equivalent to GPe) preceded and persisted during dystonic motor activity. We therefore hypothesized that on a background of slow and highly irregular and bursty neuronal activity in GP, cortical motor drive produces profound inhibition of GP as the basis for action-induced dystonia in Gunn rats. Presently, the neurotoxin ibotenate was injected locally into the motor territory of GP at one to four sites, over one to two tracts, in 19 normal rats. We found that highly circumscribed dorsal motor territory lesions reproducibly induced parkinsonism, while ventral lesions consistently produced dystonia. Post-lesioning, slow neuronal burst oscillations in the entopeduncular nucleus distinguished parkinsonian from dystonic rats. Next, we compared the deep brain stimulation contact sites in the GP internus used to treat patients with PD (n=21 implants in 12 successive patients) versus dystonia (n=16 implants in nine patients) and found the efficacious territory for ameliorating PD to be located chiefly dorsal to that for dystonia. The comparative distribution for treating PD versus dystonia was therefore anatomically consistent with that for inducing these features via GP lesions in rodents. Our collective findings thus suggest that dystonia and parkinsonism are differentially produced by pathological silencing of GPe neurons along distinct motor sub-circuits, resulting in disparate pathological basal ganglia output signaling.

Icariin, a major constituent from Epimedium brevicornum, attenuates ibotenic acid-induced excitotoxicity in rat hippocampus.

Excitotoxicity is one of the most extensively studied causes of neuronal death and plays an important role in Alzheimer's disease (AD). Icariin is a flavonoid component of a traditional Chinese medicine reported to possess a broad spectrum of pharmacological effects. The present study was designed to investigate the effects of icariin against learning and memory impairment induced by excitotoxicity. Here, we demonstrated that rats receiving intracerebroventricular injection of excitatory neurotoxin ibotenic acid exhibited impaired learning and memory. Oral administration of icariin at doses of 20 and 40mg/kg rescued behavioral performance and protected against neurotoxicity in rat hippocampus by suppressing ibotenic acid induced pro-apoptosis. Furthermore, Western blott of hippocampal specimens revealed that icariin up-regulated the expression of calbindin-D28k protein following ibotenic acid administration. Additionally, icariin inhibited mitogen-activated protein kinase (MAPK) family phosphorylation and nuclear factor kappa B (NF-κB) signaling, implicating the MAPK signaling and NF-κB signaling pathways were involved in the mechanism underlying icariin-mediated neuroprotection against ibotenic acid-induced excitotoxicity. These data suggested that icariin could be a potential agent for treatment of excitotoxicity-related diseases, including AD.

REM sleep diversity following the pedunculopontine tegmental nucleus lesion in rat.

The aim of this study was to demonstrate that two REM clusters, which emerge following bilateral pedunculopontine tegmental nucleus (PPT) lesions in rats, are two functionally distinct REM states. We performed the experiments in Wistar rats, chronically instrumented for sleep recording. Bilateral PPT lesions were produced by the microinfusion of 100 nl of 0.1M ibotenic acid (IBO). Following a recovery period of 2 weeks, we recorded their sleep for 6h. Bilateral PPT lesions were identified by NADPH - diaphorase histochemistry. We applied Fourier analysis to the signals acquired throughout the 6h recordings, and each 10s epoch was differentiated as a Wake, NREM or REM state. We analyzed the topography of the sleep/wake states architecture and their transition structure, their all state-related EEG microstructures, and the sensorimotor (SMCx) and motor (MCx) cortex REM related cortico-muscular coherences (CMCs). Bilateral PPT lesion in rats increased the likelihood of the emergence of two distinct REM sleep states, specifically expressed within the MCx: REM1 and REM2. Bilateral PPT lesion did not change the sleep/wake states architecture of the SMCx, but pathologically increased the duration of REM1 within the MCx, alongside increasing Wake/REM1/Wake and NREM/REM2/NREM transitions within both cortices. In addition, the augmented total REM SMCx EEG beta amplitude and REM1 MCx EEG theta amplitude was the underlying EEG microstructure pathology. PPT lesion induced REM1 and REM2 are differential states with regard to total EMG power, topographically distinct EEG microstructures, and locomotor drives to nuchal musculature.

Intranasal nanoparticles of basic fibroblast growth factor for brain delivery to treat Alzheimer's disease.

Disabilities caused by neurodegeneration have become one of the main causes of mortality in elderly population, with drug distribution to the brain remaining one of the most difficult challenges in the treatment of the central nervous system (CNS) diseases due to the existence of blood-brain barrier. Lectins modified polyethylene glycol-polylactide-polyglycolide (PEG-PLGA) nanoparticles could enhance the drug delivery to the brain following intranasal administration. In this study, basic fibroblast growth factor (bFGF) was entrapped in nanoparticles conjugated with Solanum tuberosum lectin (STL), which selectively binds to N-acetylglucosamine on the nasal epithelial membrane for its brain delivery. The resulting nanoparticles had uniform particle size and negative zeta potential. The brain distribution of the formulations following intranasal administration was assessed using radioisotopic tracing method. The areas under the concentration-time curve of (125)I-bFGF in the olfactory bulb, cerebrum, and cerebellum of rats following nasal application of STL modified nanoparticles (STL-bFGF-NP) were 1.79-5.17 folds of that of rats with intravenous administration, and 0.61-2.21 and 0.19-1.07 folds higher compared with intranasal solution and unmodified nanoparticles, respectively. Neuroprotective effect was evaluated using Mirror water maze task in rats with intracerebroventricular injection of ß-amyloid25-35 and ibotenic acid. The spatial learning and memory of Alzheimer's disease (AD) rats in STL-bFGF-NP group were significantly improved compared with AD model group, and were also better than other preparations. The results were consistent with the value of choline acetyltransferase activity of rat hippocampus as well as the histological observations of rat hippocampal region. The histopathology assays also confirmed the in vivo safety of STL-bFGF-NP. These results clearly indicated that STL-NP was a promising drug delivery system for peptide and protein drugs such as bFGF to enter the CNS and play the therapeutic role.

Inactivation of neuronal function in the amygdaloid region reduces tail artery blood flow alerting responses in conscious rats.

Few studies have investigated whether neuronal function in the amygdaloid complex is necessary for the occurrence of the cardiovascular response to natural (unconditioned) environmental threats. In the present investigation in conscious unrestrained Sprague-Dawley rats we inactivated neuronal function in the amygdaloid complex acutely (bilateral muscimol injections) or chronically (unilateral or bilateral ibotenic acid injections) and measured the effect on sudden falls in tail artery blood flow elicited by non-noxious salient stimuli (sympathetic cutaneous vasomotor alerting responses, SCVARs). After acute bilateral injection of vehicle (200nl Ringer's solution) the SCVAR index was 81 ± 2%, indicating that tail blood flow was reduced by 81% in response to the salient stimuli. After acute bilateral injection of muscimol (1 nmol in 200 nl of Ringer's solution) into the amygdaloid complex the SCVAR index was 49 ± 5%, indicating that tail blood flow was reduced by 49% in response to the salient stimuli (p<0.01 versus vehicle, n=7 rats for vehicle and 6 for muscimol). One week after unilateral ibotenic acid lesions, the SCVAR index was 68 ± 3%, significantly less than 90 ± 1%, the corresponding value after unilateral injection of vehicle (p<0.01, n=6 rats in each group). After bilateral ibotenic acid lesions the SCVAR index was 52 ± 4%, significantly less than 93 ± 1%, the corresponding value after bilateral injection of vehicle (p<0.001, n=6 rats in each group). Ibotenic acid caused extensive neuronal destruction of the whole amygdaloid complex, as well as lateral temporal lobe structures including the piriform cortex. Our results demonstrate that the amygdaloid complex plays an important role in mediating the tail artery vasoconstriction that occurs in rats in response to the animal's perception of a salient stimulus, redirecting blood to areas of the body with more immediate metabolic requirements.

Dorsolateral striatum and dorsal hippocampus: a serial contribution to acquisition of cue-reward associations in rats.

In laboratory rodents, procedural and declarative-like memory processes are often considered operating in dual, sometimes even competing with each other. There is evidence that the initial approach of a repetitive task first engages a hippocampus-dependent declarative-like memory system acquiring knowledge. Over repetition, there is a gradual shift towards a striatum-dependent response memory system. In the current experiment, Long-Evans male rats with bilateral, fiber-sparing ibotenic acid-induced lesions of the dorsolateral striatum or the dorsal hippocampus were trained in an olfactory associative task requiring the acquisition of both a procedural and a declarative-like memory. Rats with dorsolateral striatum lesions, and thus an intact hippocampus, were impaired on both sub-categories of memory performance. Rats with dorsal hippocampal lesions exhibited a substantial deficit in learning the declarative-like cue-reward associations, while the acquisition of the procedural memory component of the task was not affected. These data suggest that the dorsolateral striatum is required to acquire the task rule while the dorsal hippocampus is required to acquire the association between a given stimulus and its associated outcome. The finding is that the dorsolateral striatum and the dorsal hippocampus most probably contribute to successful learning of cue-reward associations in a sequential (from procedural to declarative-like memory) order using this olfactory associative learning task.

Excitotoxic perirhinal cortex lesions leave stimulus-specific habituation of suppression to lights intact.

Previous experiments demonstrate a normal decline in unconditioned responding in rats with perirhinal cortex lesions but attenuated performance on spontaneous object recognition (SOR), a finding supporting the assertion that distinct systems support these phenomena. This finding informs on the nature of these two fundamental forms of learning and may be taken as support for certain contemporary theories of memory. However, we cannot quantify the relative contributions of genuine habituation and alternative, trivial sources in response decline from effector fatigue and sensory adaptation in these demonstrations. An important implication of this problem is that previous reports may have missed perirhinal-dependent habituation. We report perirhinal cortex lesions to be without effect in rats' habituation of suppression to lights when any influence of effector fatigue and sensory adaptation is eliminated. Theoretical implications of this finding are discussed.

Excitotoxic lesions of the medial amygdala attenuate olfactory fear-potentiated startle and conditioned freezing behavior.

Conditioned fear is supported by a distributed network that prominently includes lateral and central amygdaloid nuclei. The role of corticomedial amygdaloid nuclei, including the medial nucleus (MeA), in fear acquisition or expression is not well understood. The present study demonstrates that pre-training excitotoxic lesions directed at the MeA disrupted both fear-potentiated startle (FPS) and conditioned freezing behavior elicited by re-exposure to a discrete olfactory cue. In contrast, such lesions had no effect on baseline startle reactivity or contextual FPS. These findings suggest that the MeA plays an obligatory role in either the acquisition or expression of olfactory conditioned fear, not limited by form of behavioral expression, but is not necessary for contextual conditioned fear.

Superior colliculus lesions impair threat responsiveness in infant capuchin monkeys.

The ability to react fast and efficiently in threatening situations is paramount for the survival of organisms and has been decisive in our evolutionary history. Defense mechanisms in primates rely on the fast recognition of potential predators and facial expressions of conspecifics. The neural circuitry responsible for the detection of threat is generally thought to be centered on the amygdala. Although it is a pivotal structure in the processing of emotional stimuli, the amygdala does not seem necessary for the early stages of this process. Here we show that bilateral neurotoxic lesions of the superior colliculus in infant capuchins monkeys impaired the recognition of a rubber-snake in a threat-reward conflict task. Lesioned monkeys were uninhibited by a snake in a food-reward retrieval task. Lack of inhibition in the task was observed over the course of 15 weeks. The long lasting recognition impairment of a natural predator observed here is similar to the tameness aspects of Kluver-Bucy syndrome, indicating an important role of this structure in threat recognition.

Orbitofrontal cortex and basolateral amygdala lesions result in suboptimal and dissociable reward choices on cue-guided effort in rats.

The orbitofrontal cortex (OFC) and basolateral nucleus of the amygdala (BLA) are important neural regions in responding adaptively to changes in the incentive value of reward. Recent evidence suggests these structures may be differentially engaged in effort and cue-guided choice behavior. In 2 T-maze experiments, we examined the effects of bilateral lesions of either BLA or OFC on (1) effortful choices in which rats could climb a barrier for a high reward or select a low reward with no effort and (2) effortful choices when a visual cue signaled changes in reward magnitude. In both experiments, BLA rats displayed transient work aversion, choosing the effortless low reward option. OFC rats were work averse only in the no cue conditions, displaying a pattern of attenuated recovery from the cue conditions signaling reward unavailability in the effortful arm. Control measures rule out an inability to discriminate the cue in either lesion group.

Attentional effects of lesions to the anterior cingulate cortex: how prior reinforcement influences distractibility.

Morphological changes in the anterior cingulate cortex are found in subjects with schizophrenia, attention deficit hyperactivity disorder, and obsessive-compulsive disorder. These changes are hypothesized to underlie the impairments these individuals show on tasks that require cognitive control. The anterior cingulate cortex has previously been shown to be active in situations involving high conflict, presentation of salient, distracting stimuli, and error processing, that is, situations that occur when a shift in attention or responding is required. However, there is some uncertainty as to what specific role the anterior cingulate cortex plays in these situations. The current study used converging evidence from two behavioral paradigms to determine the effects of excitotoxic lesions in the anterior cingulate cortex on executive control. The first assay tests reversal learning, attentional set formation and shifting. The second assesses sustained attention with and without distractors. Animals with anterior cingulate cortex lesions were impaired during reinforcement reversals, discriminations that required subjects to disregard previously relevant stimulus attributes and showed a more rapid decline in attentional ability than Sham-Lesioned subjects when maintaining sustained attention for extended periods of time. These results are consistent with the hypothesis that the anterior cingulate cortex is involved in attending to stimulus attributes that currently predict reinforcement in the presence of previously relevant, salient distractors and maintaining sustained attention over prolonged time on task.

Neonatal amygdala lesions alter responsiveness to objects in juvenile macaques.

The amygdala is widely recognized to play a central role in emotional processing. In nonhuman primates, the amygdala appears to be critical for generating appropriate behavioral responses in emotionally salient contexts. One common finding is that macaque monkeys that receive amygdala lesions as adults are behaviorally uninhibited in the presence of potentially dangerous objects. While control animals avoid these objects, amygdala-lesioned animals readily interact with them. Despite a large literature documenting the role of the amygdala in emotional processing in adult rhesus macaques, little research has assessed the role of the amygdala across the macaque neurodevelopmental trajectory. We assessed the behavioral responses of 3-year-old (juvenile) rhesus macaques that received bilateral ibotenic acid lesions of the amygdala or hippocampus at 2 weeks of age. Animals were presented with salient objects known to produce robust fear-related responses in macaques (e.g., snakes and reptile-like objects), mammal-like objects that included animal-like features (e.g., eyes and mouths) but not reptile-like features (e.g., scales), and non-animal objects. The visual complexity of objects was scaled to vary the objects' salience. In contrast to control and hippocampus-lesioned animals, amygdala-lesioned animals were uninhibited in the presence of potentially dangerous objects. They readily retrieved food rewards placed near these objects and physically explored the objects. Furthermore, while control and hippocampus-lesioned animals differentiated between levels of object complexity, amygdala-lesioned animals did not. Taken together, these findings suggest that early damage to the amygdala, like damage sustained during adulthood, permanently compromises emotional processing.

Familiarity-based stimulus generalization of conditioned suppression in rats is dependent on the perirhinal cortex.

We report that bilateral, excitoxic lesions of the perirhinal cortex attenuate rats' familiarity-based stimulus generalization. After surgery, rats were preexposed either to 2 auditory stimuli (A and B) or to only 1 auditory stimulus (B). Following preexposure, all rats received pairings of A and a footshock before assessment of generalized responding (conditioned suppression) to B. Sham rats' generalization was greater when preexposure was to both A and B than when preexposure was to B only. That pattern was abolished in lesioned rats, though no general deficiency was found in other measures of auditory processing. Our findings suggest that the perirhinal cortex is required for rats to encode familiarity as part of stimulus representations.

Ventromedial and medial preoptic hypothalamic ibotenic acid lesions potentiate systemic morphine analgesia in female, but not male rats.

Sex differences in systemic morphine analgesia occur with male rodents displaying significantly greater analgesic magnitudes and potencies than females. Neonatal androgenization, and to a lesser degree, adult ovariectomy enhance systemic morphine analgesia in female rats, implicating both organizational and activational effects of gonadal hormones. The neuroanatomical circuits sensitive to sex-related hormones by which females display a smaller opiate analgesic effect is not clear, but the ventromedial (VMH) and medial preoptic (MPOA) hypothalamic nuclei are critical in the monitoring of estradiol and other sex hormone levels. To assess the contribution of these nuclei to sex and adult gonadectomy differences in systemic morphine analgesia, intact male, intact female and adult ovariectomized (OVEX) female rats received bilateral saline (SAL) or ibotenic acid (IBO) microinjections into either the VMH or MPOA. Following surgeries, baseline tail-flick latencies over 120 minutes (min) were assessed over 4 days in all nine groups with intact females tested in the estrus phase of their cycle. All animals then received an ascending series of morphine (1.0, 2.5, 5.0, 7.5, 10.0mg/kg) injections 30min prior to the tail-flick test time course with 8-12 day inter-injection intervals between doses. Baseline latencies failed to differ between SAL-treated intact males and females, but were significantly higher in SAL-treated OVEX females. Both VMH IBO and MPOA IBO lesions increased baseline latencies in intact male and female rats, but not in OVEX females. SAL-treated intact males (ED(50)=4.0mg/kg) and SAL-treated OVEX females (ED(50)=3.5mg/kg) displayed significantly greater potencies of systemic morphine analgesia than SAL-treated intact females (ED(50)=6.3mg/kg), confirming previous gender and gonadectomy differences. Neither VMH IBO (ED(50)=3.7 mg/kg) nor MPOA IBO (ED(50)=4.1mg/kg) males differed from SAL-treated males in the potency of systemic morphine analgesia. In contrast, VMH IBO (ED(50)=4.1mg/kg) and MPOA IBO (ED(50)=3.5mg/kg) intact females displayed significantly greater potencies in systemic morphine analgesia than SAL-treated intact females. However, VMH IBO OVEX (ED(50)=3.5mg/kg) and MPOA IBO OVEX (ED(50)=3.9 mg/kg) failed to differ from SAL-treated OVEX females in the potency of systemic morphine analgesia. The magnitudes of systemic morphine analgesia as measured by Maximum Percentage Effect values displayed similar patterns, but lesser degrees, of effects. These data suggest that VMH and MPOA nuclei act to tonically inhibit endogenous pain-inhibitory circuits in the intact female, but not intact male brain, and that removal of circulating gonadal hormones by OVEX and/or excitotoxic destruction of these estrogen receptor accumulating nuclei disinhibit the female analgesic response to systemic morphine.

Site-specific effects on respiratory rhythm and pattern of ibotenic acid injections in the pontine respiratory group of goats.

To probe further the contributions of the rostral pons to eupneic respiratory rhythm and pattern, we tested the hypothesis that ibotenic acid (IA) injections in the pontine respiratory group (PRG) would disrupt eupneic respiratory rhythm and pattern in a site- and state-specific manner. In 15 goats, cannulas were bilaterally implanted into the rostral pontine tegmental nuclei (RPTN; n = 3), the lateral (LPBN; n = 4) or medial parabrachial nuclei (MPBN; n = 4), or the Kölliker-Fuse nucleus (KFN; n = 4). After recovery from surgery, 1- and 10-microl injections (1 wk apart) of IA were made bilaterally through the implanted cannulas during the day. Over the first 5 h after the injections, there were site-specific ventilatory effects, with increased (P < 0.05) breathing frequency in RPTN-injected goats, increased (P < 0.05) pulmonary ventilation (Vi) in LPBN-injected goats, no effect (P < 0.05) in MPBN-injected goats, and a biphasic Vi response (P < 0.05) in KFN-injected goats. This biphasic response consisted of a hyperpnea for 30 min, followed by a prolonged hypopnea and hypoventilation with marked apneas, apneusis-like breathing patterns, and/or shifts in the temporal relationships between inspiratory flow and diaphragm activity. In the awake state, 10-15 h after the 1-microl injections, the number of apneas was greater (P < 0.05) than during other studies at night. However, there were no incidences of terminal apneas. Breathing rhythm and pattern were normal 22 h after the injections. Subsequent histological analysis revealed that for goats with cannulas implanted into the KFN, there were nearly 50% fewer neurons (P < 0.05) in all three PRG subnuclei than in control goats. We conclude that in awake goats, 1) IA injections into the PRG have site-specific effects on breathing, and 2) the KFN contributes to eupneic respiratory pattern generation.

The pontine respiratory group, particularly the Kölliker-Fuse nucleus, mediates phases of the hypoxic ventilatory response in unanesthetized goats.

The objective of the present study was to test the hypothesis that, in the in vivo awake goat model, perturbation/lesion in the pontine respiratory group (PRG) would decrease the sensitivity to hypercapnia and hypoxia. The study reported herein was part of two larger studies in which cholinergic modulation in the PRG was attenuated by microdialysis of atropine and subsequently ibotenic acid injections neurotoxically lesioned the PRG. In 14 goats, cannula were bilaterally implanted into either the lateral (n=4) or medial (n=4) parabrachial nuclei or the Kölliker-Fuse nucleus (KFN, n=6). Before and after cannula implantation, microdialysis of atropine, and injection of ibotenic acid, hypercapnic and hypoxic ventilatory sensitivities were assessed. Hypercapnic sensitivity was assessed by three 5-min periods at 3, 5, and 7% inspired CO2. In all groups of goats, CO2 sensitivity was unaffected (P>0.05) by any PRG perturbations/lesions. Hypoxic sensitivity was assessed with a 30-min period at 10.8% inspired O2. The response to hypoxia was typically triphasic, with a phase 1 increase in pulmonary ventilation, a phase 2 roll-off, and a phase 3 prolonged increase associated with shivering and increased metabolic rate and body temperature. In all groups of goats, the phase 1 of the hypoxic ventilatory responses was unaffected by any PRG perturbations/lesions, and there were no consistent effects on the phase 2 responses. However, in the KFN group of goats, the phase 3 ventilatory, shivering, metabolic rate, and temperature responses were markedly attenuated after the atropine dialysis studies, and the attenuation persisted after the ibotenic acid studies. These findings support an integrative or modulatory role for the KFN in the phase 3 responses to hypoxia.

Distinct contributions of the hippocampus and medial prefrontal cortex to the "what-where-when" components of episodic-like memory in mice.

There is a current controversy regarding whether non-human animals have a capacity for episodic memory, defined by the ability to remember what happened and where and when it occurred. It is also unclear which brain structures support the "what," "where," and "when" aspects of episodic memory. Here we addressed these issues by testing episodic memory in mice, using an object recognition task that has previously been employed to assess the "what," "where," and "when" components of recognition memory. Whereas intact mice remembered which objects they had explored, as well as when and where they were experienced, mice with damage to the hippocampus were impaired on all three components of the task. In contrast, animals with medial prefrontal cortical lesions were selectively impaired on the "where" component of the task, but had intact memory for "what" and "when." These results are consistent with the hypothesis that the hippocampus integrates the "what," "where," and "when" features of unique experiences, whereas the prefrontal cortex makes a more selective contribution to retrieving source information about where events occurred.