Bao-Ming Li

Roles of NMDA NR2B Subtype Receptor in Prefrontal Long-Term Potentiation and Contextual Fear Memory

Cortical plasticity is thought to be important for the establishment, consolidation, and retrieval of permanent memory. Hippocampal long-term potentiation (LTP), a cellular mechanism of learning and memory, requires the activation of glutamate N-methyl-D-aspartate (NMDA) receptors. In particular, it has been suggested that NR2A-containing NMDA receptors are involved in LTP induction, whereas NR2B-containing receptors are involved in LTD induction in the hippocampus. However, LTP in the prefrontal cortex is less well characterized than in the hippocampus. Here we report that the activation of the NR2B and NR2A subunits of the NMDA receptor is critical for the induction of cingulate LTP, regardless of the induction protocol. Furthermore, pharmacological or genetic blockade of the NR2B subunit in the cingulate cortex impaired the formation of early contextual fear memory. Our results demonstrate that the NR2B subunit of the NMDA receptor in the prefrontal cortex is critically involved in both LTP and contextual memory.

Deficit in long‐term contextual fear memory induced by blockade of β‐adrenoceptors in hippocampal CA1 region

The present study investigated the effects of intra‐CA1 infusion of d,l‐propranolol, the β‐adrenergic antagonist, on memory for contextual fear conditioning. d,l‐Propranolol administered 5 min (‘0 h’) postconditioning impaired long‐term but not short‐term contextual fear memory, while it was ineffective when administered 6 h postconditioning, suggesting that there is a time window for β‐adrenoceptors to play a role. Thus, we conclude that β‐adrenoceptors in area CA1 are involved in regulating consolidation of contextual fear memory, with ‘0 h’ but not 6 h post‐training, a sensitive time point for the β‐adrenergic involvement.

Selective deficit in no-go performance induced by blockade of prefrontal cortical α2-adrenoceptors in monkeys

&NA; Two monkeys (Macacamulatta) were trained tomake a go response (go to touch a computer screen) when a red signal (go signal) was presented or a no‐go response (inhibit the screen‐touching action) when a green signal (no‐go signal) was given. The &agr;2‐adrenergic antagonist yohimbinewas infused locally, bilaterally and continuously for 8 days into the prefrontal cortex (PFC) by using mini‐osmotic pump.The no‐go but not go performancewas selectively impaired during the 8 ‐day administration of yohimbine: the monkeys showed an inability to inhibit the touching response to the no‐go signal, indicating that there was a deficit in the inhibitory ability of the animals. Similar infusion of saline into the same cortical area was without effect. The present study provides behavioral pharmacological evidence that &agr;2‐adrenoceptors in the PFC are involved in the neural mechanisms underlying response inhibition.

Glucocorticoid receptors in the basolateral nucleus of amygdala are required for postreactivation reconsolidation of auditory fear memory.

It is well known that initial consolidation requires de novo gene transcription and protein synthesis in order for memory to become stable. The consolidated memory again becomes labile and temporarily sensitive to disruption when retrieved, requiring a reconsolidation process to become permanent. Although it is well established that glucocorticoid receptors (GR) in the basolateral nucleus of amygdala (BLA) are required for consolidation of fear memory, little is known about their role in reconsolidation of fear memory. In the present study, we first examined the effect of a GR antagonist on postconditioning consolidation of auditory fear memory (AFM). Intra‐BLA infusion of the GR antagonist RU486 0 h postconditioning impaired long‐term AFM, leaving short‐term AFM intact. RU486 had no effect if infusion was performed 6 h postconditioning. We then investigated the effect of the RU486 treatment on postretrieval reconsolidation of AFM. Severe amnesia took place when RU486 was infused into the BLA 0 h postretrieval (reactivation) of AFM, regardless of whether the retrieval was performed 1 day or 10 days postconditioning. RU486 produced no amnesia if the memory retrieval was omitted or if the drug was administered 6 h postretrieval. Treatment with RU486 0 h postretrieval produced no deficit in postretrieval short‐term memory but impaired postretrieval long‐term memory, and the amnesia exhibited no spontaneous recovery 6 days after retrieval. The present results provide strong evidence that glucocorticoid receptors in the BLA are required for reconsolidation as well as consolidation of AFM.

SNAP-25 in hippocampal CA1 region is involved in memory consolidation

As a synaptosomal protein, SNAP‐25 plays a role in a number of neuronal functions including axonal growth, dendrite formation, fusion of synaptic vesicles with membrane and the expression of long‐term potentiation (LTP) in the hippocampus. Using a learning/memory behavior screening, we identified SNAP‐25 as one of the differentially expressed genes in the hippocampus upon behavioral training. The inhibition of SNAP‐25 with intracerebroventricular antisense oligonucleotide caused a deficit in long‐ but not short‐term memory for step‐down inhibitory avoidance. Intra‐CA1 infusion of the SNAP‐25 antisense oligonucleotide impaired long‐term contextual fear memory and spatial memory and interfered with the LTP of synaptic transmission in the CA1 region. The inhibitory effect on LTP was not mediated by a pre‐synaptic mechanism because paired pulse facilitation of synaptic transmission was not affected after administration of the antisense oligonucleotide. Together, the results suggest that SNAP‐25 in the CA1 region is involved in memory consolidation.

Stimulation of α2-Adrenoceptors Suppresses Excitatory Synaptic Transmission in the Medial Prefrontal Cortex of Rat

Stimulation of α2-, especially α2A-adrenoceptor (AR), in the prefrontal cortex (PFC) produces a beneficial effect on cognitive functions such as working memory. α2-Adrenergic agonists like clonidine and guanfacine have been used experimentally and clinically for treatment of psychiatric disorders such as attention-deficit/hyperactivity disorder (ADHD) and schizophrenia. However, the neurophysiological actions of α2-ARs in the PFC are poorly understood. In the present study, we recorded field excitatory post-synaptic potential (fEPSP) and evoked excitatory post-synaptic current (eEPSC) in the medial prefrontal cortex (mPFC) of rats, using in vivo field-potential recording and in vitro whole-cell patch-clamp recording techniques, and examined the effects of the α2-AR agonist clonidine and the selective α2A-AR agonist guanfacine on fEPSP and eEPSC. Systemic or intra-mPFC application of clonidine or guanfacine significantly reduced fEPSP in the mPFC, either in anesthetized or freely moving rats. Consistently, bath-application of guanfacine suppressed eEPSC in layer V/VI pyramidal neurons, and this effect was blocked by the α2-AR antagonist yohimbine or the Gi inhibitor NF023. Moreover, treatment with guanfacine had no effect on paired-pulse facilitation (PPF) of fEPSP and eEPSC. The present study provides the first electrophysiological evidence that stimulation of α2A-AR inhibits excitatory synaptic transmission in the mPFC through a post-synaptic mechanism.

Induction- and conditioning-protocol dependent involvement of NR2B-containing NMDA receptors in synaptic potentiation and contextual fear memory in the hippocampal CA1 region of rats

Long-term potentiation (LTP) in the hippocampal CA1 region requires the activation of N-methyl-D-aspartate receptors (NMDARs). Studies using genetic and pharmacological approaches have reported inconsistent results of the requirement of NR2B-containing NMDARs in LTP in the CA1 region. Pharmacological studies showed that NR2B-containing NMDARs are not required for LTP, while genetic studies reported that over-expression of NR2B-NMDARs enhances LTP and hippocampus-dependent memory. Here, we provide evidence showing that the functional role of NR2B-NMDARs in hippocampal LTP and memory depends on LTP-inducing and behavior-conditioning protocols. Inhibition of NR2B-NMDARs with the NR2B selective antagonist ifenprodil or Ro25-6981 suppressed LTP induced by spike-timing protocol, with no impact on LTP induced by pairing protocol or two-train high-frequency stimulation (HFS) protocol. Inhibition of NR2B-NMDARs did not affect the late phase LTP induced by four-train HFS. Ca2+ imaging showed that there was difference in kinetics of intracellular Ca2+ signals induced by spiking-timing and pairing protocols. Pre-training intra-CA1 infusion of ifenprodil or Ro25-6981 impaired the contextual fear memory induced by five CS-US pairings, with no effect on the memory induced by one CS-US pairing.

Enhanced cocaine self-administration in adult rats with adolescent isolation experience.

It is widely accepted that early environmental influences may affect the behavior of adult animals and their responses to psychotropic drugs. Rearing animals in isolation is a relevant paradigm for studying early life stress and for understanding the development of certain neurological and psychiatric diseases. The present study evaluated the effect of adolescent isolation on intravenous cocaine self-administration in adult rats. Male Sprague-Dawley rats were raised from postnatal day 22 to 55 either alone (isolated) or in groups of four per cage (grouped). Then, rats were trained for cocaine self-administration. Our results showed that both isolated and grouped rats acquired stable cocaine self-administration during 5 days of self-administration training. Numbers of both lever presses and cocaine infusions in isolated rats were significantly more than those in grouped rats. Especially, numbers of incorrect lever presses in isolated rats were significantly more than those in grouped rats. In addition, the intervals of inter-reinforcement for cocaine in isolated rats were significantly shorter as compared with grouped rats. These results indicate that rats with adolescent isolation experience have enhanced cocaine self-administration behavior.

Genetic enhancement of trace fear memory and cingulate potentiation in mice overexpressing Ca2+/calmodulin-dependent protein kinase IV

Long‐term potentiation (LTP) is a key cellular model for studying mechanisms for learning and memory. Previous studies reported that the Ca2+/calmodulin‐dependent protein kinase IV (CaMKIV) is critical for gene regulation, and behavioral learning and memory. Less is known about the roles of CaMKIV in cortical plasticity and trace fear memory. Here we have found that LTP was significantly enhanced in the anterior cingulate cortex (ACC) of the mice overexpressing CaMKIV. By contrast, neither α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid (AMPA) receptor‐mediated basal excitatory synaptic transmission nor N‐methyl‐d‐aspartate (NMDA) receptor‐mediated excitatory postsynaptic currents were affected. Furthermore, paired‐pulse ratio in the transgenic mice is normal. In behavioral tests, we found that the CaMKIV transgenic mice exhibited significant enhancement in trace fear memory, while the acute sensory thresholds were not affected. Our results provide strong evidence that forebrain CaMKIV contributes to trace fear memory by enhancing synaptic potentiation in the ACC.

Pallidal activity is involved in visuomotor association learning in monkeys

In order to examine whether the basal ganglia are involved in arbitrary visuomotor association, we recorded neuronal activity in the internal segment of the globus pallidus (GPi) of monkeys during a conditional visuomotor learning task. Two monkeys were presented a cueing visual stimulus, and following a delay period required to push, pull or turn a manipulator according to the cue. GPi neurons showed changes in activity during the delay period when the animals performed the task on the basis of a familiar stimulus–response association. Those changes in delay activity were enhanced as the monkeys were learning a new visuomotor association. The enhancement of the changes was selective to a following response. These results suggest that the basal ganglia are involved in arbitrary visuomotor association, especially during the learning of new associations.