Contribution of the prefrontal cortex and basolateral amygdala to behavioral decision-making under reward/punishment conflict.

RATIONALE: Control of reward-seeking behavior under conditions of punishment is an important function for survival. OBJECTIVES AND METHODS: We designed a task in which rats could choose to either press a lever and obtain a food pellet accompanied by a footshock or refrain from pressing the lever to avoid footshock, in response to tone presentation. In the task, footshock intensity steadily increased, and the task was terminated when the lever press probability reached < 25% (last intensity). Rats were trained until the last intensity was stable. Subsequently, we investigated the effects of the pharmacological inactivation of the ventromedial prefrontal cortex (vmPFC), lateral orbitofrontal cortex (lOFC), and basolateral amygdala (BLA) on task performance. RESULTS: Bilateral inactivation of the vmPFC, lOFC, and BLA did not alter lever press responses at the early stage of the task. The number of lever presses increased following vmPFC and BLA inactivation but decreased following lOFC inactivation during the later stage of the task. The last intensity was elevated by vmPFC or BLA inactivation but lowered by lOFC inactivation. Disconnection of the vmPFC-BLA pathway induced behavioral alterations that were similar to vmPFC or BLA inactivation. Inactivation of any regions did not alter footshock sensitivity and anxiety levels. CONCLUSIONS: Our results demonstrate a strong role of the vmPFC and BLA and their interactions in reward restraint to avoid punishment and a prominent role of the lOFC in reward-seeking under reward/punishment conflict situations.

The loop neural circuit between the medial prefrontal cortex and the amygdala in the rat brain.

A major neuronal basis underlying emotion regulation is the inhibitory influence of the medial prefrontal cortex (mPFC) on amygdalar neurons. However, in spite of the importance of mPFC neuronal activities in emotion regulation, little is known about the inputs modulating activity of mPFC neurons projecting to the amygdala. To gain insight into dense reciprocal connections between mPFC and amygdala, we investigated neural circuits between these brain regions using electrophysiological techniques. We found that mPFC neurons were antidromically driven mainly by stimulation of the central nucleus of the amygdala (CeA), rather than the posterior part of the basolateral nucleus of the amygdala (pBLA), whereas pBLA, but not CeA, stimulation evoked orthodromic excitatory and inhibitory responses. mPFC neurons antidromically driven by CeA stimulation showed excitatory or inhibitory responses to pBLA stimulation. These findings indicate the existence of a functional neural loop between amygdala and mPFC, pointing to an amygdalar self-control system.

Early-life stress induces anxiety-like behaviors and activity imbalances in the medial prefrontal cortex and amygdala in adult rats.

Early-life stress increases the prevalence of psychiatric diseases associated with emotional dysregulation. Emotional regulation requires the inhibitory influence of the medial prefrontal cortex (mPFC) on amygdalar activity, and dysfunction of this system is believed to induce anxiety. Because mPFC and amygdala have dense reciprocal connections and projections between them continue to develop until adolescence, early-life stress may impair the function of this circuit and cause emotional dysregulation. We examined the effects of stress during circuit development on anxiety-like behaviors, neural activities in the mPFC and amygdala, and impulse transmission in the mPFC-amygdala circuit in adult rats. Early-life stress, unpredictable stress twice a day for 12 days following early weaning, increased anxiety-like behaviors in the open-field and elevated plus-maze tests. In the open-field test, stress altered Fos expression in the mPFC and amygdala. Compared to non-stressed rats, which were exposed to neither unpredictable stress nor early weaning, stressed rats exhibited decreased Fos expression in the right superficial layers of the infralimbic cortex and increased Fos expression in the right basolateral amygdala and both sides of the central amygdala. Electrophysiological analysis revealed that excitatory latencies of mPFC neurons to amygdalar stimulation in stressed rats were significantly longer than control rats in the right, but not left, hemisphere. Stress had no effect on excitatory latencies of amygdalar neurons to mPFC stimulation in the mPFC-amygdala circuits in the both hemisphere. These data suggest that early-life stress impairs the mPFC-amygdala circuit development, resulting in imbalanced mPFC and amygdala activities and anxiety-like behaviors.

Hyperlocomotor activity and stress vulnerability during adulthood induced by social isolation after early weaning are prevented by voluntary running exercise before normal weaning period.

In rodents, the disruption of social-rearing conditions before normal weaning induces emotional behavioral abnormalities, such as anxiety, motor activity dysregulation, and stress vulnerability. The beneficial effects of exercise after normal weaning on emotional regulation have been well documented. However, effects of exercise before normal weaning on emotion have not been reported. We examined whether voluntary wheel running (R) during social isolation after early weaning (early weaning/isolation; EI) from postnatal day (PD) 14-30 could prevent EI-induced emotional behavioral abnormalities in Sprague-Dawley rats. Compared with control rats reared with their dam and siblings until PD30, rats performed R during EI (EI+R) and EI rats demonstrated greater locomotion and lower grooming activity in the open-field test (OFT) during the juvenile period. Juvenile EI ± R rats showed greater learned helplessness (LH) after exposure to inescapable stress (IS; electric foot shock) than IS-exposed control and EI rats. In contrast, EI rats showed increased locomotion in the OFT and LH after exposure to IS compared with control rats during adulthood; this was not observed in EI ± R rats. Both EI and EI ± R rats exhibited greater rearing activity in the OFT than controls during adulthood. EI did not increase anxiety in the OFT and elevated plus-maze. These results suggested that R during EI until normal weaning prevented some of the EI-induced behavioral abnormalities, including hyperlocomotor activity and greater LH, during adulthood but not in the juvenile period.

[Influence on the physical characteristics of medical color liquid crystal displays with increase in aperture ratio].

We measured the physical characteristics of 2-million(2M)and 3-million(3M)color liquid crystal displays(LCD)whose aperture ratio was increased and compared them with conventional models. The results showed the influence of the increased aperture ratio on the physical characteristics of the LCDs. We evaluated resolution by means of modulation transfer function(MTF)and evaluated granularity by means of noise power spectrum(NPS). Each of the measurements was done with a high-resolution single-lens reflex-type digital camera. A decrease of MTF depending on sub-pixel structures was recognized. A decrease in the cross sub-pixel direction was recognized in the 2M model, and a decrease in the sub-pixel direction was recognized in the 3M model. As for NPS, a reduction was recognized in the sub-pixel and the cross sub-pixel direction in both models. As a result, an improvement in granularity was recognized. The improvement in granularity was large with the color LCDs whose aperture ratio was increased. The increase of an aperture ratio influenced both MTF and NPS, and the results depended on the shape and size of the sub-pixel cells.

Basolateral amygdala neurons facilitate reward-seeking behavior by exciting nucleus accumbens neurons.

Both the nucleus accumbens (NAc) and basolateral amygdala (BLA) contribute to learned behavioral choice. Neurons in both structures that encode reward-predictive cues may underlie the decision to respond to such cues, but the neural circuits by which the BLA influences reward-seeking behavior have not been established. Here, we test the hypothesis that the BLA drives NAc neuronal responses to reward-predictive cues. First, using a disconnection experiment, we show that the BLA and dopamine projections to the NAc interact to promote the reward-seeking behavioral response. Next, we demonstrate that BLA neuronal responses to cues precede those of NAc neurons and that cue-evoked excitation of NAc neurons depends on BLA input. These results indicate that BLA input is required for dopamine to enhance the cue-evoked firing of NAc neurons and that this enhanced firing promotes reward-seeking behavior.

Dorsomedial prefrontal cortex contribution to behavioral and nucleus accumbens neuronal responses to incentive cues.

Cue-elicited phasic changes in firing of nucleus accumbens (NAc) neurons can facilitate reward-seeking behavior. Here, we test the hypothesis that the medial prefrontal cortex (mPFC), which sends a dense glutamatergic projection to the NAc core, contributes to NAc neuronal firing responses to reward-predictive cues. Rats trained to perform an operant response to a cue for sucrose were implanted with recording electrodes in the core of the NAc and microinjection cannulas in the dorsal mPFC (dmPFC). The cue-evoked firing of NAc neurons was reduced by bilateral injection of GABA(A) and GABA(B) agonists into the dmPFC concomitant with loss of behavioral responding to the cue. In addition, unilateral dmPFC inactivation reduced ipsilateral cue excitations and contralateral cue inhibitions. These findings indicate that cue-evoked excitations and inhibitions of NAc core neurons depend on dmPFC projections to the NAc and that these phasic changes contribute to the behavioral response to reward-predictive cues.

13-cis-retinoic acid alters the cellular morphology of slice-cultured serotonergic neurons in the rat.

Retinoids influence cellular processes such as differentiation, proliferation and apoptosis via retinoic acid receptor (RAR) and retinoid X receptor (RXR), and have therapeutic applications in several cancers and dermatologic diseases. Recent reports indicate that depression occasionally occurs in patients using the acne drug Accutane, the active component of which is 13-cis-retinoic acid (13-cis-RA). Although impairment of serotonin (5-HT)-expressing neurons, including morphologic changes, is thought to be associated with depressive symptoms, the effects of 13-cis-RA on 5-HT neurons have not been examined. The present study demonstrated that 13-cis-RA alters the morphology of 5-HT neurons in cultured rat midbrain slices. The 13-cis-RA-induced changes were partially blocked by RXR and RAR antagonists. Furthermore, cotreatment with RAR and RXR agonists altered the morphology of 5-HT neurons to a greater extent than the individual application of each agonist. The morphologic changes were completely blocked by RXR antagonist, whereas RAR antagonist partially blocked the effects. These results suggest that 13-cis-RA exerts its action on slice-cultured 5-HT neurons, at least in part, through specific retinoid receptors. Moreover, RXR has a greater influence on the morphology of 5-HT neurons than RAR. The receptor-mediated actions of 13-cis-RA presented here may provide a clue for further research on depression associated with the use of 13-cis-RA.

Interferon-alpha reduces the density of monoaminergic axons in the rat brain.

Interferon-alpha commonly induces depressive symptoms in clinical populations; however, the mechanism by which this occurs is unclear. Recent studies suggest that the degeneration of axons containing serotonin and noradrenaline is involved in the pathophysiology of depression. The present immunohistochemical study shows that the density of serotonergic axons decreased in the ventral medial prefrontal cortex and amygdala in the interferon-alpha-treated animals. Additionally, interferon-alpha induced decreases in the density of noradrenergic axons in the dorsal medial prefrontal cortex, ventral medial prefrontal cortex, and dentate gyrus. These results support the hypothesis that long-term administration of interferon-alpha causes the degeneration of monoaminergic axons in specific brain regions, which might be associated with depressive symptoms occurring in interferon-alpha-treated patients.

Selective rapid eye movement sleep deprivation impairs the maintenance of long-term potentiation in the rat hippocampus.

Rapid eye movement (REM) sleep deprivation (RSD) is known to impair learning and memory. Previous studies have demonstrated that RSD induces an impairment of hippocampal long-term potentiation (LTP). In most of these studies, RSD was set up prior to LTP induction. In this work, we focused on RSD after LTP induction. We investigated the effect of RSD for 24-48 h after induction of LTP in the dentate gyrus on LTP maintenance and whether a REM rebound after 48 h RSD affected LTP. RSD rats were deprived of REM sleep by stroking their backs using a brush, whereas control rats were allowed to sleep freely. Another control group of rats was awoken during non-REM sleep (NRS) under the same conditions (NRS group). REM-deprived rats displayed a faster decay of population spike amplitudes compared with the control and NRS groups over a 24-h recording time. After 48 h RSD, there was no difference in the population spike amplitudes before or after 4 h of release from RSD. These results suggest that REM sleep after LTP induction in the dentate gyrus plays an essential role in LTP maintenance, whereas a REM rebound does not restore the RSD-induced impairment of LTP.

Ventral hippocampal neurons project axons simultaneously to the medial prefrontal cortex and amygdala in the rat.

The ventral hippocampus (VH) may have an important role in spatial memory processes and emotional behaviors through connections with the medial prefrontal cortex (mPFC) and amygdala. Although the mPFC and amygdala receive afferent projections from the VH, it has not been determined whether the individual VH neurons project to both the mPFC and the amygdala. In this study, antidromic responses to the mPFC and amygdala stimulation were evoked in single VH neurons. In addition, VH neurons were retrogradely double-labeled with fluorescent tracers injected in the mPFC and amygdala. VH neurons projecting to both the mPFC and amygdala were predominantly located in the subiculum and CA1 and bifurcated near or at the soma. Our anatomical and electrophysiological evidence for the presence of VH neurons projecting to both the mPFC and amygdala provides a previously unrecognized pathway from the hippocampus that simultaneously activates the mPFC and amygdala.

Essential role of D1 but not D2 receptors in methamphetamine-induced impairment of long-term potentiation in hippocampal-prefrontal cortex pathway.

Methamphetamine (MA) abuse induces deficits in cognitive performance that are related to dysfunction of the prefrontal cortex (PFC). The medial portion of the prefrontal cortex (mPFC) in rats that is crucial for cognitive function has been shown to undergo long-term potentiation (LTP) in the projections from the hippocampus. However, no study has been performed to evaluate the influence of MA on synaptic plasticity in the hippocampal-mPFC pathways. In the present experiments, we investigated the effects of repeated MA administration on hippocampal-mPFC LTP, together with MA-induced stereotyped behaviors. Repeated MA administration produced behavioral sensitization and LTP impairment in the hippocampal-mPFC pathways. The MA-induced impairment of hippocampal-mPFC LTP was prevented by the pretreatment of dopamine 1 (D1) but not dopamine 2 (D2) receptor antagonists, while D1 and D2 receptor antagonists attenuated the MA-induced stereotyped behaviors. These findings suggest that D1 receptors are crucial for the MA-induced deterioration of synaptic plasticity in the hippocampal-mPFC circuits. Impairment of LTP associated with D1 receptor dysfunction may underlie cognitive deficits in MA-dependent subjects.

Convergence and interaction of hippocampal and amygdalar projections within the prefrontal cortex in the rat.

The orbital and medial prefrontal cortex (OMPFC) receives inputs from the CA1/subicular (CA1/S) region of the ventral hippocampus and the basolateral nucleus of the amygdala (BLA). Despite many studies about these projections, little is known as to how CA1/S and BLA inputs converge and interact within the OMPFC. Extracellular recordings of single-unit activity in the OMPFC were performed in sodium pentobarbitone-anesthetized rats. OMPFC neurons driven by CA1/S or BLA stimulation were more frequently encountered in the ventral portion of the prelimbic (v-PrL) and infralimbic cortex (IL). OMPFC neurons showing excitatory convergence of both inputs from the CA1/S and BLA were also located predominantly in the v-PrL and IL. The excitatory latencies of these neurons from both the CA1/S and BLA revealed almost identical values. Excitatory responses of OMPFC neurons to CA1/S (or BLA) stimulation were markedly augmented by simultaneous BLA (or CA1/S) stimulation, whereas the inhibitory influence of the BLA (or CA1/S) on CA1/S-induced (or BLA-induced) excitation was apparent when BLA (or CA1/S) stimulation was given 20-40 msec before CA1/S (or BLA) stimulation. Similar results were also observed when reciprocal connections between the CA1/S and BLA were severed to exclude the influences of these connections on one another. From these studies, we concluded that excitatory and inhibitory inputs from the hippocampus and amygdala converge and interact in the v-PrL and IL. Furthermore, the results indicate that simultaneous activation of hippocampal and amygdalar neurons may be important for amplification of OMPFC neuronal activity.

Cortical spreading depression affects Fos expression in the hypothalamic paraventricular nucleus and the cerebral cortex of both hemispheres.

The present experiments were performed to clarify the brain sites whose activity is affected exclusively by cortical spreading depression (CoSD). For this purpose, Fos protein, a product of an immediate early gene, was used as a marker of neuronal activation. Because Fos can be induced by many manipulations such as stress stimuli, we verified CoSD-induced Fos expression by excluding the influence of other factors such as anaesthesia and surgical manipulation. CoSD was induced by applying a KCl solution directly to the dura mater over the cerebral cortex, and Fos expression in the brain was assessed by immunohistochemistry using antibodies against Fos protein. We found that during CoSD, Fos expression was increased specifically in the magnocellular region of the hypothalamic paraventricular nucleus (PVN), as well as in the ipsilateral cortex, whereas reduced Fos expression was observed in both the parvocellular region of the PVN and the whole cortex contralateral to the CoSD site. Consistent with the reduced Fos expression, approximately 40% of neurons in the contralateral cortex revealed a suppression of electrical activity during CoSD. These results suggest that in addition to the ipsilateral cortex, CoSD affects Fos expression exclusively in the PVN and the contralateral cortex.