Low-frequency stimulation induces a pathway-specific late phase of LTP in the amygdala that is mediated by PKA and dependent on protein synthesis

Activity-dependent changes in synaptic efficacy are thought to be the key cellular mechanism for the formation and storage of both explicit and implicit memory. Different patterns of stimulation can elicit different changes in the efficiency on excitatory synaptic transmission. Here, we examined the synaptic changes in the amygdala of adult mice produced by low-frequency stimulation (1 Hz, 15 min, LFS). We first compared the synaptic changes induced by LFS in three different synaptic pathways of amygdala: cortical–lateral amygdala, thalamic–lateral amygdala, and lateral–basolateral amygdala pathways. We find that the plastic changes induced by LFS are different between synaptic pathways. Low-frequency stimulation selectively elicits a slow onset and protein synthesis-dependent late-phase LTP in the cortical–lateral amygdala pathway, but not in the thalamic–lateral or lateral–basolateral pathways. We next analyzed LTP induced by LFS in the cortical–lateral amygdala pathway and found that three PKA-coupling neurotransmitter receptors are involved: 5-HT4, Dopamine D1, and β-adrenergic receptors. Antagonists of these receptors block the LFS L-LTP, but the effects of agonists of these receptors are clearly different. These results indicate that the threshold for the induction of LFS L-LTP is different among these pathways and that the maintenance of LFS L-LTP requires a cross-talk among multiple neurotransmitters.     

Contextual and auditory fear conditioning are mediated by the lateral, basal, and central amygdaloid nuclei in rats

A large body of literature implicates the amygdala in Pavlovian fear conditioning. In this study, we examined the contribution of individual amygdaloid nuclei to contextual and auditory fear conditioning in rats. Prior to fear conditioning, rats received a large electrolytic lesion of the amygdala in one hemisphere, and a nucleus-specific neurotoxic lesion in the contralateral hemisphere. Neurotoxic lesions targeted either the lateral nucleus (LA), basolateral and basomedial nuclei (basal nuclei), or central nucleus (CE) of the amygdala. LA and CE lesions attenuated freezing to both contextual and auditory conditional stimuli (CSs). Lesions of the basal nuclei produced deficits in contextual and auditory fear conditioning only when the damage extended into the anterior divisions of the basal nuclei; damage limited to the posterior divisions of the basal nuclei did not significantly impair conditioning to either auditory or contextual CS. These effects were typically not lateralized, although neurotoxic lesions of the posterior divisions of the basal nuclei had greater effects on contextual fear conditioning when the contralateral electrolytic lesion was placed in the right hemisphere. These results indicate that there is significant overlap within the amygdala in the neural pathways mediating fear conditioning to contextual and acoustic CS, and that these forms of learning are not anatomically dissociable at the level of amygdaloid nuclei.     

Projection of the Magnocellular Red Nucleus to the Region of the Accessory Abducens Nucleus in the Rabbit

The projection of the magnocellular red nucleus (RNm) to the region of the accessory abducens nucleus (AABD) was traced in rabbit using the bidirectional tracer wheat germ agglutinin-horseradish peroxidase (WGA-HRP). In one set of animals, recordings of antidromic responses from RNm neurons elicited by electrical stimulation of the rubrospinal tract were used to localize injections of WGA-HRP for orthograde labeling of RNm terminals. In a different set of animals, horseradish peroxidase was injected into the retractor bulbi muscle to retrogradely label motoneurons of the AABD. The positions of RNm fibers and terminals were examined and compared to the locations and distribution of AABD cell bodies and labeled dendrites. Analyses revealed that along the entire rostrocaudal extent of the AABD, RNm efferents terminate primarily lateral to, or in the lateral aspects of, labeled motoneurons. For the rostral AABD, RNm efferents terminate only lateral to the nucleus. Although the terminals are not positioned to contact cell bodies of the AABD, they could overlap with dendrites that extend in the lateral direction. RNm efferents terminate more extensively within the posterior AABD, overlapping within both dendritic and cell body regions of the nucleus. Even in this posterior region, however, RNm efferents were distributed primarily over the lateral half of the nucleus. These data show that RNm can monosynaptically influence the AABD, through primarily its lateral and posterior aspects. Our findings also show that a major target of RNm efferents is the reticular cell population located lateral to the AABD, suggesting that the RNm also may affect AABD motoneuronal output indirectly through its projection to reticular cells.     

Neurochemical mechanisms underlying amygdaloid modulation of aggressive behavior in the cat

Studies designed to determine the respective roles of substance P, excitatory amino acids, and enkephalins in amygdaloid modulation of defensive rage behavior in the cat are presented. The basic design of these studies involved three stages. In stage I, cannula electrodes for stimulation and drug infusion were implanted into medial hypothalamic or midbrain periaqueductal gray (PAG) sites from which defensive rage behavior could be elicited. Then, a stimulating electrode was implanted into a site within the medial, basal, or central nuclear complex from which modulation of the defensive rage response could be obtained. Amygdaloid modulation of defensive rage was determined in the following manner: it employed the paradigm of dual stimulation in which comparisons were made of response latencies between alternate trials of dual (i. e., amygdala = medial hypothalamus [or PAG]) and single stimulation of the hypothalamus or PAG alone. Thus, stage I established the baseline level ofmodulation (i. e., facilitation or suppression of defensive rage) in the predrug stimulation period. In stage II, a selective or nonselective receptor antagonist for a given transmitter system was administered either peripherally or intracerebrally at the defensive rage site, after which time the same dual stimulation paradigm was then repeated over the ensuing 180 min postinjection period in order to determine the effects of drug delivery upon amygdaloid modulation of defensive rage. Stage III of the study took place at the completion of the pharmacological testing phase. The retrograde axonal tracer, Fluoro-Gold, was microinjected into the defensive rage site within the medial hypothalamus or PAG, and following a 6-14 day survival period, animals were sacrificed and brains were processed for histological and immunocytochemical analyses for the neurotransmitters noted above. This procedure thus permitted identification of cells within the amygdala which were labeled retrogradely and which were also immunostained positively for substance P, excitatory amino acids, or enkephalin. For studies involving substance P, defensive rage was elicited from the medial hypothalamus and for studies examining the roles of excitatory amino acids and enkephalin, defensive rage was elicited from the PAG. In the first study, facilitation of hypothalamically elicited defensive rage was obtained with dual stimulation of the medial nucleus of the amygdala. In separate experiments, the selective NK₁ non-peptide antagonist, CP 96,345, was administered both peripherally as well as intracerebrally into the hypothalamic defensive rage sites in doses of 0.5-4.0 mg/kg (i. p.) and 0.5-2.5 nmol (i. c.). Following drug delivery, the facilitatory effects of medial amygdaloid stimulation were blocked in a dose- and time-dependent manner in which the effects were noted as early as 5 min postinjection. The maximum drug dose (4.0 mg/kg) employed for peripheral administration resulted in a 42% reduction in the facilitatory effects of the medical amygdala (P < 0.002). This drug, when microinjected directly into medial hypothalamic defensive rage sites at the maximum dose level of 2.5 nmol, resulted in an 84% reduction of the suppressive effects of amygdaloid stimulation (P < 0.5) at 5 min postinjection. In the next study, an N-methyl-D-aspartate (NMDA) antagonist, DL-α-amino-7-phosphonoheptanoic acid (AP-7), was administered either peripherally (0.1-1.0 mg/kg) or intracerebrally (0.2 and 2.0 nmol) into PAG defensive rage sites. Facilitation of defensive rage behavior, which was observed following dual stimulation of the basal amygdala and PAG, was significantly reduced by either route of drug administration in a dose- and time-dependent manner. At the maximum dose level of peripheral administration, AP-7 reduced amygdaloid facilitation of defensive rage by 63% (P < 0.001) for 60 min, postinjection. A smaller (i. e., 19%) but still significant (P < 0.05) reduction in facilitation was obtained following intracerebral administration of the drug. In a third study, the non-selective opioid receptor antagonist, naloxone (27.5 nmol), infused directly into PAG defensive rage sites, totally blocked the suppressive effects of central amygdaloid stimulation for a period of 30 min (P < 0.05) in a dose- and time-dependent manner. The anatomical phase of this study revealed the following relationships: 1) that large numbers of neurons projecting to the medial hypothalamus from the medial amygdala immunoreact positively for substance P; 2) that neurons projecting to the PAG from the basal complex of amygdala immunoreact positively for glutamate and aspartate; and 3) that neurons located within the central nucleus of the amygdala which project to the PAG immunoreact positively for met-enkephalin. Collectively, these observations provide new evidence which characterizes the likely neurotransmitters linked with specific amygdaloid pathways subserving the modulation of defensive rage behavior in the cat.     

Stress-induced relapse to drug seeking in the rat: role of the bed nucleus of the stria terminalis and amygdala

There is growing interest in the role that the bed nucleus of the stria terminalis (BNST) and central nucleus of the amygdala (CeA), components of the extended amygdala, play in drug addiction. Within the BNST and CeA, there is an extensive system of intrinsic, primarily GABAergic, interconnections known to synthesize a variety of neuropeptides, including corticotrophin-releasing factor (CRF). The actions of CRF at extrahypothalamic sites,including the BNST and CeA, have been implicated in stress responses and in the aversive effects of withdrawal from drugs of abuse. Most recently, we have shown a critical role for extrahypothalamic CRF in stress-induced reinstatement of drug seeking in rats. In attempting to determine which brain circuitry mediates the effect of stress on relapse and, more specifically, where in the brain CRF acts to initiate the behaviours involved in relapse, we focused on the BNST and CeA. In the present paper, we summarize studies we have conducted that explore the role of these brain sites in stress-induced relapse to heroin and cocaine seeking, and then consider how our findings can be understood within the more general context of what is known about the role of the BNST and CeA in stress-related and general approach behaviours, such as drug seeking.     

Delta-sleep inducing peptide (DSIP) and ACTH (4-10) analogue influence fos-induction in the limbic structures of the rat brain under emotional stress

The effects of the ACTH (4-10) analogue, ACTH (4-7)-Pro-Gly-Pro, and delta-sleep inducing peptide (DSIP) on the induction of Fos immunoreactivity in the hypothalamic parvocellular paraventricular nucleus (pPVN) and limbic brain regions were studied in Wistar rats with high (resistant) or low (predisposed) resistance to emotional stress, predicted from differences in their open-field behaviour. Fos-immunoreactive (Fos-IR) cells were counted in brain sections automatically with a computer-based image analyser. Under basal conditions, Fos-IR cell numbers were greater in the pPVN in the predisposed rats, but were lower than in the resistant rats in the basolateral amygdala and medial and lateral septum. Intraperitoneal DSIP injection (30 μg/kg) increased basal Fos-IR cell number in the pPVN and lateral septum in resistant rats, with no effects in predisposed rats. ACTH (4-10) analogue (50 μg/kg)increased Fos expression in the pPVN in both resistant and predisposed rats, with essentially no effects in the basolateral amygdala or medial and lateral septum. Emotional stress (60 min restraint and intermittent subcutaneous electrical shocks) increased Fos expression in the pPVN and medial and lateral septum similarly in predisposed and resistant rats, but in the basolateral amygdala in only the predisposed rats. Intraperitoneal DSIP injection reduced the increases in Fos-IR cell number after emotional stress, particularly in predisposed rats. In predisposed rats DSIP decreased the number of Fos-IR cells in the pPVN and the medial and lateral septum, with no change in the basolateral amygdala. In resistant rats, DSIP decreased Fos expression only in the lateral septum. ACTH (4-10) analogue injection inhibited stress-induced Fos expression in the pPVN and the medial septum, but only in predisposed rats. The experiments indicate that DSIP and ACTH (4-10) analogue reduce pPVN and limbic neurone responses to emotional stress in the rats predisposed to emotional stress; the effects on Fos expression may play a role in the biological activities of these peptides.     

Hippocampal regulation of context-dependent neuronal activity in the lateral amygdala

Pavlovian fear conditioning is a robust and enduring form of emotional learning that provides an ideal model system for studying contextual regulation of memory retrieval. After extinction the expression of fear conditional responses (CRs) is context-specific: A conditional stimulus (CS) elicits greater conditional responding outside compared with inside the extinction context. Dorsal hippocampal inactivation with muscimol attenuates context-specific CR expression. We have previously shown that CS-elicited spike firing in the lateral nucleus of the amygdala is context-specific after extinction. The present study examines whether dorsal hippocampal inactivation with muscimol disrupts context-specific firing in the lateral amygdala. We conditioned rats to two separate auditory CSs and then extinguished each CS in separate and distinct contexts. Thereafter, single-unit activity and conditional freezing were tested to one CS in both extinction contexts after saline or muscimol infusion into the dorsal hippocampus. After saline infusion, rats froze more to the CS when it was presented outside of its extinction context, but froze equally in both contexts after muscimol infusion. In parallel with the behavior, lateral nucleus neurons exhibited context-dependent firing to extinguished CSs, and hippocampal inactivation disrupted this activity pattern. These data reveal a novel role for the hippocampus in regulating the context-specific firing of lateral amygdala neurons after fear memory extinction.     

Damage to the lateral and central, but not other, amygdaloid nuclei prevents the acquisition of auditory fear conditioning

It is well established that the amygdala plays an essential role in Pavlovian fear conditioning, with the lateral nucleus serving as the interface with sensory systems that transmit the conditioned stimulus and the central nucleus as the link with motor regions that control conditioned fear responses. The lateral nucleus connects with the central nucleus directly and by way of several other amygdala regions, including the basal, accessory basal, and medial nuclei. To determine which of these regions is necessary, and thus whether conditioning requires the direct or one of the indirect intra-amygdala pathways, we made lesions in rats of the lateral, central, basal, accessory basal, and medial nuclei, as well as combined lesions of the basal and accessory basal nuclei and of the entire amygdala. Animals subsequently underwent fear conditioning trials in which an auditory conditioned stimulus was paired with a footshock unconditioned stimulus. Animals that received lesions of the lateral or central nucleus, or of the entire amygdala, were dramatically impaired, whereas the other lesions had little effect. These findings show that only the lateral and central nuclei are necessary for the acquisition of conditioned fear response to an auditory conditioned stimulus.     

Activation of the cannabinoid receptor type 1 decreases glutamatergic and GABAergic synaptic transmission in the lateral amygdala of the mouse

The endogenous cannabinoid system has been shown recently to play a crucial role in the extinction of aversive memories. As the amygdala is presumably involved in this process, we investigated the effects of the cannabinoid receptor agonist WIN 55,212-2 (WIN-2) on synaptic transmission in the lateral amygdala (LA) of wild-type and cannabinoid receptor type 1 (CB1)-deficient mice. Extracellular field potential recordings and patch-clamp experiments were performed in an in vitro slice preparation. We found that WIN-2 reduces basal synaptic transmission and pharmacologically isolated AMPA receptor- and GABA_A receptor-mediated postsynaptic currents in wild-type, but not in CB1-deficient mice. These results indicate that, in the LA, cannabinoids modulate both excitatory and inhibitory synaptic transmission via CB1. WIN-2-induced changes of paired-pulse ratio and of spontaneous and miniature postsynaptic currents suggest a presynaptic site of action. Inhibition of G_i/o proteins and blockade of voltage-dependent and G protein-gated inwardly rectifying K⁺ channels inhibited WIN-2 action on basal synaptic transmission. In contrast, modulation of the adenylyl cyclase-protein kinase A pathway, and blockade of presynaptic N- and P/Q- or of postsynaptic L- and R/T-type voltage-gated Ca²⁺ channels did not affect WIN-2 effects. Our results indicate that the mechanisms underlying cannabinoid action in the LA partly resemble those observed in the nucleus accumbens and differ from those described for the hippocampus.     

The bed nucleus of the stria terminalis is required for the expression of contextual but not auditory freezing in rats with basolateral amygdala lesions

Previous data suggest that overtraining can overcome fear conditioning deficits in rats with lesions of the basolateral complex of the amygdala (BLA). We have previously shown that the central nucleus of the amygdala (CEA) is essential for the acquisition and expression of conditional fear to both contextual and auditory conditioned stimuli (CSs) after overtraining. This provides strong evidence that the CEA can compensate for the loss of the BLA. Another brain area that may compensate for the loss of the BLA is the bed nucleus of the stria terminalis (BNST). We explored this possibility by examining the consequences of lesions or reversible inactivation of the BNST on the expression of overtrained fear in rats with BLA lesions. We demonstrate that lesions or inactivation of the BNST block the expression of freezing to the conditioning context, but not to an auditory conditional stimulus. These results reveal that the BNST has a critical role in the expression of contextual fear, but not fear to an auditory CS, and is therefore not the essential locus of compensation for fear learning in the absence of the BLA.     

Kindling-induced changes in plasticity of the rat amygdala and hippocampus

Temporal lobe epilepsy (TLE) is often accompanied by interictal behavioral abnormalities, such as fear and memory impairment. To identify possible underlying substrates, we analyzed long-term synaptic plasticity in two relevant brain regions, the lateral amygdala (LA) and the CA1 region of the hippocampus, in the kindling model of epilepsy. Wistar rats were kindled through daily administration of brief electrical stimulations to the left basolateral nucleus of the amygdala. Field potential recordings were performed in slices obtained from kindled rats 48 h after the last induced seizure, and in slices from sham-implanted and nonimplanted controls. Kindling resulted in a significant impairment of long-term potentiation (LTP) in both the LA and the CA1, the magnitude of which was dependent on the number of prior stage V seizures. Saturation of CA1-LTP, assessed through repeated spaced delivery of high-frequency stimulation, occurred at lower levels in kindled compared to sham-implanted animals, consistent with the hypothesis of reduced capacity of further synaptic strengthening. Furthermore, theta pulse stimulation elicited long-term depression in the amygdala in nonimplanted and sham-implanted controls, whereas the same stimulation protocol stimulation caused LTP in kindled rats. In conclusion, kindling differentially affects the magnitude, saturation, and polarity of LTP in the CA1 and LA, respectively, most likely indicating an activity-dependent mechanism in the context of synaptic metaplasticity.     

A neurophysiologic model for aggressive behavior in the cat

A neurophysiologic model for aggessive behavior in the cat is proposed. Stimulus-bound and seizure-bound aggression was evaluated in relation to limbic and basal ganglia induced seizures (after-discharges). Electrically induced limbic and basal ganglia afterdischarges were used because they are known to implicate septohypothalamic sites from which aggression can be elicited by direct stimulation. The occurrence of behavioral aggression is correlated with the discharge characteristics of a single discharging system and with two interacting discharging systems. Aggression is composed of autonomic and somato-motor components which poses relatively low and high thresholds, respectively, for their activation. Aggression occurring during a combined septum and amygdala discharge was more intense and prolonged than with a septum discharge alone. Participation of a slow frequency discharging basal ganglia system activated seizurebound aggression in an otherwise nonaggressive limbic seizure. The limbic and basal ganglia stimulations and after-discharges lowered the excitability threshold of the aggression system and made it more vulnerable to being activated by external stimuli, such as visual and auditory stimuli. These observations are reminiscent of patients with aggressive behavior associated with psychomotor seizures.     

Processing emotional pictures and words: Effects of valence and arousal

There is considerable debate regarding the extent to which limbic regions respond differentially to items with different valences (positive or negative) or to different stimulus types (pictures or words). In the present event-related fMRI study, 21 participants viewed words and pictures that were neutral, negative, or positive. Negative and positive items were equated on arousal. The participants rated each item for whether it depicted or described something animate or inanimate or something common or uncommon. For both pictures and words, the amygdala, dorsomedial prefrontal cortex (PFC), and ventromedial PFC responded equally to all high-arousal items, regardless of valence. Laterality effects in the amygdala were based on the stimulus type (word 5 left, picture 5 bilateral). Valence effects were most apparent when the individuals processed pictures, and the results revealed a lateral/medial distinction within the PFC: The lateral PFC responded differentially to negative items, whereas the medial PFC was more engaged during the processing of positive pictures.     

Phosphorylation of ERK/MAP kinase is required for long-term potentiation in anatomically restricted regions of the lateral amygdala in vivo

We have previously shown that the extracellular signal-regulated kinase/mitogen-activated protein kinase (ERK/ MAPK) is transiently activated in anatomically restricted regions of the lateral amygdala (LA) following Pavlovian fear conditioning and that blockade of ERK/MAPK activation in the LA impairs both fear memory consolidation and long-term potentiation (LTP) in the amygdala, in vitro. The present experiments evaluated the role of the ERK/MAPK signaling cascade in LTP at thalamo-LA input synapses, in vivo. We first show that ERK/MAPK is transiently activated/phosphorylated in the LA at 5 min, but not 15 or 60 min, after high-frequency, but not low-frequency, stimulation of the auditory thalamus. ERK activation induced by LTP-inducing stimulation was anatomically restricted to the same regions of the LA previously shown to exhibit ERK regulation following fear conditioning. We next show that intra-LA infusion of U0126, an inhibitor of ERK/MAPK activation, impairs LTP at thalamo-LA input synapses. Collectively, results demonstrate that ERK/MAPK activation is necessary for synaptic plasticity in anatomically defined regions of the LA, in vivo.     

情景变换诱发已消退恐惧记忆重现的神经环路

暴露疗法是治疗创伤后应激障碍的主要行为疗法。当被试反复暴露于可引起恐惧反应的条件刺激(如白噪音), 但却不伴有非条件刺激(如足底电击)时, 恐惧记忆将被消退, 形成消退记忆。但恐惧记忆并未从根本上被擦除, 当被试在消退训练以外的情景暴露于条件刺激时, 已消退的恐惧记忆将会重现。海马、内侧前额叶皮层、杏仁核等脑区及其相互连接的神经环路是情景诱发恐惧记忆重现的生理基础。情景变化诱发恐惧记忆重现过程中, 海马可能是通过直接投射至杏仁核基底核、杏仁核外侧核或通过边缘前皮质间接调控杏仁核基底核、杏仁核外侧核的功能, 产生恐惧反应。     

Impaired long-term potentiation and enhanced neuronal excitability in the amygdala of CaV1.3 knockout mice

Previously, we demonstrated that mice in which the gene for the L-type voltage-gated calcium channel Ca_V1.3 is deleted (Ca_V1.3 knockout mice) exhibit an impaired ability to consolidate contextually-conditioned fear. Given that this form of Pavlovian fear conditioning is critically dependent on the basolateral complex of the amygdala (BLA), we were interested in the mechanisms by which Ca_V1.3 contributes to BLA neurophysiology. In the present study, we used in vitro amygdala slices prepared from Ca_V1.3 knockout mice and wild-type littermates to explore the role of Ca_V1.3 in long-term potentiation (LTP) and intrinsic neuronal excitability in the BLA. We found that LTP in the lateral nucleus (LA) of the BLA, induced by high-frequency stimulation of the external capsule, was significantly reduced in Ca_V1.3 knockout mice. Additionally, we found that BLA principal neurons from Ca_V1.3 knockout mice were hyperexcitable, exhibiting significant increases in firing rates and decreased interspike intervals in response to prolonged somatic depolarization. This aberrant increase in neuronal excitability appears to be at least in part due to a concomitant reduction in the slow component of the post-burst afterhyperpolarization. Together, these results demonstrate altered neuronal function in the BLA of Ca_V1.3 knockout mice which may account for the impaired ability of these mice to consolidate contextually-conditioned fear.     

Impact of infralimbic inputs on intercalated amygdala neurons: a biophysical modeling study

Intercalated (ITC) amygdala neurons regulate fear expression by controlling impulse traffic between the input (basolateral amygdala; BLA) and output (central nucleus; Ce) stations of the amygdala for conditioned fear responses. Previously, stimulation of the infralimbic (IL) cortex was found to reduce fear expression and the responsiveness of Ce neurons to BLA inputs. These effects were hypothesized to result from the activation of ITC cells projecting to Ce. However, ITC cells inhibit each other, leading to the question of how IL inputs could overcome the inter-ITC inhibition to regulate the responses of Ce neurons to aversive conditioned stimuli (CSs). To investigate this, we first developed a compartmental model of a single ITC cell that could reproduce their bistable electroresponsive properties, as observed experimentally. Next, we generated an ITC network that implemented the experimentally observed short-term synaptic plasticity of inhibitory inter-ITC connections. Model experiments showed that strongly adaptive CS-related BLA inputs elicited persistent responses in ITC cells despite the presence of inhibitory interconnections. The sustained CS-evoked activity of ITC cells resulted from an unusual slowly deinactivating K(+) current. Finally, over a wide range of stimulation strengths, brief IL activation caused a marked increase in the firing rate of ITC neurons, leading to a persistent decrease in Ce output, despite inter-ITC inhibition. Simulations revealed that this effect depended on the bistable properties and synaptic heterogeneity of ITC neurons. These results support the notion that IL inputs are in a strategic position to control extinction of conditioned fear via the activation of ITC neurons.     

Transcranial direct current stimulation and visual perception

Membrane potentials and spike sequences represent the basic modes of cerebral information processing. Both can be externally modulated in humans by quite specific techniques: transcranial direct current stimulation (tDCS) and repetitive transcranial magnetic stimulation (rTMS). These methods induce reversible circumscribed cortical excitability changes, either excitatory or inhibitory, outlasting stimulation in time. Experimental pharmacological interventions may selectively enhance the duration of the aftereffects. Whereas rTMS induces externally triggered changes in the neuronal spiking pattern and interrupts or excites neuronal firing in a spatially and temporally restricted fashion, tDCS modulates the spontaneous firing rates of neurons by changing resting-membrane potential. The easiest and most common way of evaluating the cortical excitability changes is by applying TMS to the motor cortex, since it allows reproducible quantification through the motor-evoked potential. Threshold determinations at the visual cortex or psychophysical methods usually require repeated and longer measurements and thus more time for each data set. Here, results derived from the use of tDCS in visual perception, including contrast as well as motion detection and visuo-motor coordination and learning, are summarised. It is demonstrated that visual functions can be transiently altered by tDCS, as has been shown for the motor cortex previously. Up- and down-regulation of different cortical areas by tDCS is likely to open a new branch in the field of visual psychophysics.     

Activation of CB1 specifically located on GABAergic interneurons inhibits LTD in the lateral amygdala

Previously, we found that in the lateral amygdala (LA) of the mouse, WIN55,212-2 decreases both glutamatergic and GABAergic synaptic transmission via activation of the cannabinoid receptor type 1 (CB1), yet produces an overall reduction of neuronal excitability. This suggests that the effects on excitatory transmission override those on inhibitory transmission. Here we show that CB1 activation by WIN55,212-2 and Delta(9)-THC inhibits long-term depression (LTD) of basal synaptic transmission in the LA, induced by low-frequency stimulation (LFS; 900 pulses/1 Hz). The CB1 agonist WIN55,212-2 blocked LTD via G(i/o) proteins, activation of inwardly rectifying K+ channels (K(ir)s), inhibition of the adenylate cyclase-protein kinase A (PKA) pathway, and PKA-dependent inhibition of voltage-gated N-type Ca2+ channels (N-type VGCCs). Interestingly, WIN55,212-2 effects on LTD were abolished in CB1 knock-out mice (CB1-KO), and in conditional mutants lacking CB1 expression only in GABAergic interneurons, but were still present in mutants lacking CB1 in principal forebrain neurons. LTD induction per se was unaffected by the CB1 antagonist SR141716A and was normally expressed in CB1-KO as well as in both conditional CB1 mutants. Our data demonstrate that activation of CB1 specifically located on GABAergic interneurons inhibits LTD in the LA. These findings suggest that CB1 expressed on either glutamatergic or GABAergic neurons play a differential role in the control of synaptic transmission and plasticity.     

The legacy of the silver methods and the new anatomy of the basal forebrain: implications for neuropsychiatry and drug abuse

The first part of the paper highlights the remarkable legacy of the silver methods, with special emphasis on the travails and opportunities offered by the various Nauta methods and their modifications. When the tracer methods based on axoplasmic flow were introduced in the early 1970s, they were exploited on a backdrop of a basic anatomical framework, which had already been established through the tracing of the major CNS pathways by the aid of the silver methods, especially the widely used Nauta-Gygax methods and their modifications. Some of the silver methods that were developed in the late 1960s for the staining of degenerating boutons (e.g. the Fink-Heimer method and de Olmos cupric silver method) provided the necessary technical improvements that eventually led to a new and more productive way to look at the basal forebrain functional/anatomical organization; if it was not for the silver methods, we would in all likelihood still be promoting the nebulous notion of the substantia innominata rather than the concepts of the ventral striatopallidal system and the extended amygdala. The discovery and elaboration of these two macroanatomical systems symbolize what might deservedly be called the "new anatomy" of the basal forebrain. Following a review of the critical experiments which led to the development of the new anatomy of the basal forebrain, its topography in the human is reviewed in drawings of an abbreviated series of coronal sections. The discovery of the ventral striatopallidal system and its thalamic projection to the mediodorsal thalamus rather than to the ventral anterior-ventral lateral thalamic complex ushered in the idea of parallel cortico-subcortical reentrant circuits, which to a large extent has replaced the limbic system as a theoretical framework for neuropsychiatric disorders. The extended amygdala, which appears as a large ring formation around the internal capsule, is still controversial in some quarters, although it is slowly but surely making its way into the general neuroscience literature, especially in the field of addictive disorders. The ventral striatopallidal system and the extended amygdala are interwoven in a complex fashion with the basal nucleus of Meynert within the basal forebrain. Together, these three systems represent important output channels for so-called "limbic" forebrain regions, especially orbitomedial prefrontal cortex and medial temporal lobe structures, which are increasingly implicated in major neuropsychiatric disorders.