Increased fear- and stress-related anxiety-like behavior in mice lacking tuberoinfundibular peptide of 39 residues.

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.

Leptin-regulated endocannabinoids are involved in maintaining food intake.

Leptin is the primary signal through which the hypothalamus senses nutritional state and modulates food intake and energy balance. Leptin reduces food intake by upregulating anorexigenic (appetite-reducing) neuropeptides, such as alpha-melanocyte-stimulating hormone, and downregulating orexigenic (appetite-stimulating) factors, primarily neuropeptide Y. Genetic defects in anorexigenic signalling, such as mutations in the melanocortin-4 (ref. 5) or leptin receptors, cause obesity. However, alternative orexigenic pathways maintain food intake in mice deficient in neuropeptide Y. CB1 cannabinoid receptors and the endocannabinoids anandamide and 2-arachidonoyl glycerol are present in the hypothalamus, and marijuana and anandamide stimulate food intake. Here we show that following temporary food restriction, CB1 receptor knockout mice eat less than their wild-type littermates, and the CB1 antagonist SR141716A reduces food intake in wild-type but not knockout mice. Furthermore, defective leptin signalling is associated with elevated hypothalamic, but not cerebellar, levels of endocannabinoids in obese db/db and ob/ob mice and Zucker rats. Acute leptin treatment of normal rats and ob/ob mice reduces anandamide and 2-arachidonoyl glycerol in the hypothalamus. These findings indicate that endocannabinoids in the hypothalamus may tonically activate CB1 receptors to maintain food intake and form part of the neural circuitry regulated by leptin.