Previous studies have shown that biochemical changes that occur in the amygdala during fear conditioning in vivo are similar to those occur during long term potentiation (LTP) in vitro. Electrophoretic mobility shift assay of nuclear extracts from startle-potentiated rats showed a selective increase in the amygdala of nuclear factor-B (NF-B) DNA binding activity. Supershift experiments further indicated that p65 and p50 subunits but not c-Rel were involved in DNA binding. The protein levels of IB-␣ were reduced by treatments that reliably induced LTP in this area of the brain. This was accompanied by a decrease of NF-B in the cytoplasm concomitant with an increase in the nucleus. Quantitative analysis of IB kinase activity demonstrated that fear training led to an increase in kinase activity, and this effect was inhibited by thalidomide. Paralleled behavioral tests revealed that thalidomide inhibited fear-potentiated startle. Intra-amygdala administration of B decoy DNA prior to training impaired fear-potentiated startle as well as LTP induction. Similarly, NF-B inhibitors blocked IB-␣ degradation and startle response. These results provide the first evidence of a requirement of NF-B activation in the amygdala for consolidation of fear memory.It is generally believed that consolidation of long term memory in mammalian brain and long term facilitation in Aplysia require new protein synthesis (1-3). Newly synthesized proteins are thought to deposit at the synapses that have been tagged by prior activity to encode enduring changes in synaptic strength (4, 5). However, despite the importance of new protein synthesis for memory consolidation, little is known about signaling pathways leading to protein translation in neurons.NF-B, originally identified as a regulator of immunoglobulin light chain gene expression, is a DNA-binding factor that functions as a dimer. Five mammalian members of the family have been identified; p50/NF-B1, p65/RelA, c-Rel, RelB, and p52/NF-B2 (6). NF-B was localized mainly to the cytoplasm in an inactive form bound to an inhibitory protein termed IB (7). Upon stimulation by extracellular inducers, IB was rapidly phosphorylated by the IB kinase (IKK) complex on the serine residues 32 and 36. This phosphorylation led to the ubiquitination and subsequent degradation of IB by the proteasome followed by nuclear translocation of NF-B (8 -11). Once translocated to the nucleus, NF-B bound cognate DNA sequences and activated transcription of specific target genes, the majority of which encoded proteins important in immunity and inflammation (12-15). Apart from its role in hematopoiesis, accumulated evidence indicates that NF-B is involved in neuroprotection or neurodegeneration, depending on the particular system under investigation and the NF-B subunits that became activated (16 -18). Furthermore, a recent study implicated that NF-B played an important role in the synaptic plasticity, because pretreatment of hippocampal slices with B decoy DNA prevented induction of long term depression (LTD) 1 and s...