**Background:** Maternal overnutrition is associated with increased risk of obesity and metabolic dysfunction in offspring. The lateral hypothalamic area (LHA) is a critical node regulating feeding and energy balance, and the BNST→LHA pathway (GABAergic projection from bed nucleus of the stria terminalis to LHA glutamatergic neurons) mediates feeding behavior. However, the circuit-level mechanisms by which maternal obesity alters feeding circuitry remain largely unexplored.
**Methods:** Female C57BL/6J mice (n=6 per group) were given ad libitum access to either high-fat diet (HFD, Bio-Serv #F3282: 5.49 kcal/g, 60% fat calories) plus chow or taste-matched low-fat diet (LFD, Bio-Serv F4031: 3.93 kcal/g, 16% fat calories) plus chow for 6 weeks prior to mating, and diets were maintained through gestation and lactation. Offspring (mHFD and mLFD) were weighed at postnatal days 10, 15, and 21, then weaned onto standard chow. Acute HFD intake was tested at ~p40 (24-hr access to chow, LFD, and HFD simultaneously). Chronic HFD intake was tested at ~p60 (3 weeks ad libitum HFD plus chow). A subset of mice received bilateral BNST injections of AAV5-hsyn-ChR2-eYFP for channelrhodopsin-assisted circuit mapping. Whole-cell current-clamp and voltage-clamp recordings were performed ex vivo in LHA brain slices to assess neuronal excitability and synaptic connectivity. Spontaneous and evoked EPSCs and IPSCs were recorded from LHA neurons receiving monosynaptic BNST input (→BNSTLHA neurons) and from unconnected LHA neurons.
**Key Results:** mHFD pups had significantly increased body weight during lactation at p10, p14, and p21 (two-way ANOVA, main effect of Group: F(1,45)=42.83, p=4.8e-8; interaction: F(3,135)=5.02, p=0.0025; Sidak's p<0.0001). Body weights normalized by p50. In acute feeding assays, mHFD mice consumed more HFD calories per gram body weight at 24 hr (t(41)=2.26, p=0.029) and had higher total caloric intake (t(41)=2.12, p=0.04). During chronic HFD access, mHFD mice consumed significantly more calories (two-way ANOVA, main effect of Group: F(1,11)=5.99, p=0.03; interaction: F(2,22)=7.06, p=0.004; Sidak's p<0.05) and gained more weight (two-way ANOVA, main effect of Group: F(1,44)=37.48, p=2.2e-7; interaction: F(2,88)=36.69, p=2.6e-12; Sidak's p<0.0001). LHA neurons from mHFD mice showed increased firing in response to positive current injection (>200 pA; two-way ANOVA, interaction: F(15,720)=2.32, p=0.003). No differences were observed in resting membrane potential, action potential characteristics, or rheobase. Of 70 recorded LHA neurons, 60% (42/70) received synaptic input from BNST; 86% (36/42) exhibited light-evoked IPSCs and 14% (6/42) exhibited EPSCs. Evoked IPSC amplitudes were similar between groups (Welch's t-test: t(18.53)=0.74, p=0.47) but were significantly predicted by juvenile growth rate (r=-0.72, p=0.01). In →BNSTLHA neurons, mHFD mice showed increased EPSC amplitude (t(39)=2.35, p=0.02) and increased excitation/inhibition balance (Welch's t-test: t(38.33)=2.37, p=0.02). EPSC amplitude was predicted by perinatal growth rate (r=-0.64, p=0.03). No differences in synaptic input were observed in LHA neurons not receiving BNST input. mHFD pups had lower survival (50%) than mLFD pups (90%) (Fisher's exact test, p=9.9e-7).
**Clinical Implications:** This study identifies a specific neural pathway (BNST→LHA) that is functionally rewired by maternal overnutrition, providing a mechanistic link between early-life nutritional environment and adult obesity susceptibility. The finding that early-life growth rate predicts synaptic changes suggests that developmental trajectories may identify at-risk individuals. The results suggest that targeted manipulations of the BNST→LHA pathway or glutamatergic signaling within the LHA could potentially mitigate the effects of perinatal overnutrition, though further research is needed. The study also highlights that both male and female offspring are affected, with females showing more pronounced weight gain during chronic HFD access.