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Tuberoinfundibular peptide of 39 residues (TIP39) is synthesized by two groups of neurons, one in the subparafascicular area at the caudal end of the thalamus and the other in the medial paralemniscal nucleus within the lateral brainstem. The subparafascicular TIP39 neurons project to a number of brain regions involved in emotional responses, and these regions contain a matching distribution of a receptor for TIP39, the parathyroid hormone 2 receptor (PTH2-R). We have now evaluated the involvement of TIP39 in anxiety-related behaviors using mice with targeted null mutation of the TIP39 gene (Tifp39). Tifp39(-/-) mice (TIP39-KO) did not significantly differ from wild-type (WT) littermates in the open field, light/dark exploration and elevated plus-maze assays under standard test conditions. However, the TIP39-KO engaged in more active defensive burying in the shock-probe test. In addition, when tested under high illumination or after restraint, TIP39-KO displayed significantly greater anxiety-like behavior in the elevated plus-maze than WT. In a Pavlovian fear-conditioning paradigm, TIP39-KO froze more than WT during training and during tone and context recall but showed normal fear extinction. Disruption of TIP39 projections to the medial prefrontal cortex, lateral septum, bed nucleus of the stria terminalis, hypothalamus and amygdala likely account for the fear- and anxiety-related phenotype of TIP39-KO. Current data support the hypothesis that TIP39 modulates anxiety-related behaviors following environmental provocation.