Developmental Responses of the Lateral Hypothalamus to Leptin in Neonatal Rats, and its Implications for the Development of Functional Connections with the Ventral Tegmental Area

Food intake is regulated by a close communication between the hypothalamus and the mesocorticolimbic pathways, which are still developing during the perinatal period in the rat, and are known targets for peripheral metabolic hormones such as leptin. A key region for this communication is the lateral hypothalamus (LH), although the onset of leptin responsiveness in the LH is unknown. We examined the activation of cellular signalling molecules in identified LH neurones on postnatal day (PND)10 and 16 and determined whether leptin directly targets orexin A (ORX‐A) or neurotensin (NT) LH neurones through the detection of leptin receptors (ObRb) mRNA on these neurones. Next, using retrograde labelling in PND6 pups, we tested whether phenotypically identified neurones of the LH that respond to leptin project to ventral tegmental area (VTA) neurones. Leptin significantly induced phosphorylated extracellular signal‐regulated kinase (pERK)1/2 and phosphorylated signal transducer activator of transcription (pSTAT)3 in the LH on PND16, whereas, on PND10, modest pERK1/2‐ and sparse pSTAT3‐positive cells were identified. On PND16, most pERK1/2‐activated neurones contain ORX‐A and leptin‐induced pSTAT3 was observed in other unidentified neurones. Afferents to the VTA were observed on PND6, including a large input from the LH, which contained both ORX‐A‐positive and non‐ORX‐A neurones, with some of these ORX‐A neurones being activated by leptin treatment. Leptin receptor (ObRb) mRNA in the LH did not colocalise with ORX‐A neurones on PND10, and only a few NT‐positive neurones displayed ObRb mRNA expression. Thus, functional responsiveness to leptin in LH neurones is only partially achieved prior to the onset of independent feeding on PND16, and ORX‐A neurones are indirectly activated by leptin. The presence of anatomical connections between the LH and the VTA in the first week of life, prior to the development of leptin responsiveness in both structures, suggests that tissue responsiveness to leptin, rather than the maturation of neuronal connections, critically regulates the onset of independent feeding.